Vaccines Have Serious Side Effects

The Revised Authoritative Guide To Vaccine Legal Exemptions

Comprehensive, authoritative information about vaccine exemptions you can trust, from Alan Phillips, J.D., a leading vaccine rights attorney with years of experience helping clients throughout the U.S. legally avoid vaccines in a wide variety of vaccine-refusal settings. Critical details for parents, students, immigrants, healthcare employees, military personnel and contractors, agencies, attorneys and clientsvirtually anyone concerned with legally avoiding vaccines in the United States. This Guide provides and explains: Important background information about the legal system; How state and federal statutes, regulations, constitutions and legal precedent interact to define the boundaries of your legal exemption rights; How to deal with local authorities and to avoid mistakes that cost others their exemption; Where legal technicalities and practical reality differand what to do about it; More here...

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Tumorderived Stress Protein Preparations As Tumor Vaccines

Most current strategies of tumor vaccination aim at the activation of a T-cell response against tumors. One reason for this is the observation that immunologically induced tumor regressions in inbred mice are mediated by T cells. The second reason is the knowledge that during carcinogenesis and due to genetic instability multiple random and transformation-related genetic changes take place in tumor cells. These changes lead to the expression of altered proteins and in consequence to the formation of altered peptide epitopes, against which immunological tolerance has not been developed and which can be recognized by T cells of the host. It has been proposed that the antigenicity of a tumor cell is the consequence of a multitude of altered epitopes, which lead to an individual antigenic finger print for each tumor 39 , However, tumor cells exert a multiplicity of mechanisms to circumvent an effective primary activation of T cells lack of costimulation 40 , secretion of immunosuppressive...

C pneumoniae Vaccine Development

Obstacles in achieving a C. pneumoniae vaccine. Chlamydial infections often recur or remain persistent, indicating absence of sterilizing immunity. However, studies in an experimental model of infection with the related organism C. trachomatis indicate a short-lived immunity after natural infection. The resistance to genital chlamydial diseases augments with age (and hence exposure), and vaccination with inactivated organisms produce a short-lived protection against ocular challenge. The immune response against chlamydia can mediate pathogenesis, as exemplified by the sensitization to a more severe disease in individuals vaccinated against C. trachomatis. It is speculated that this may be due to the presence of proinflammatory molecules such as LPS or cross-reactive antigens with host molecules. Protective or adverse effects may not only depend on specific antigen (s) but also on innate immune mechanisms that are mobilized by the infection. Diverse innate immune mechanisms are known...

True Chronic Myeloid Leukemia Specific Antigen Vaccines

Tumor Associated Antigen Definition

The BCR-ABL-derived p210 protein and particularly the alternative b3a2 or b2a2 peptide epitope at its fusion point is the most obvious CML-specific target, and thus was first explored for a vaccine strategy. p210 is exclusive to the CML clone, and the sequences of amino acids contained in the b3a2 and b2a2 junctional regions represent unique tumor-specific determinants, which can be exploited for an immunological attack against the tumor cell (11). Recent data support the hypothesis that peptides binding HLA with moderate-to-high affinity are capable of stimulating T-cells after natural processing and cell surface presentation within the cleft of the appropriate HLA molecule. Within the p210 b3a2 breakpoint sequence, five junctional peptides were found to be capable of binding to certain HLA class I and class II molecules and were shown to elicit in vitro a specific T-cell response both in normal donors (12) and in CML patients (13). After these initial observations, p210 b3a2...

Chronic Myeloid Leukemia Cell Derived Multi Antigen Vaccines

Heat Shock Protein Vaccines Heat shock proteins (HSPs) are ubiquitous protective intracellular molecules induced by cellular stress, which act as chaperones for peptides. HSPs isolated from tumor cells carry an array of tumor-specific peptides capable of inducing immune responses. In fact, purified HSP-peptide complexes have been demonstrated to activate CD8+ and CD4+ lymphocytes to induce innate immune responses, including natural killer (NK) cell activation, cytokine secretion, and induce maturation of DCs (33). In a phase I trial, vaccinations with patient-specific autologous leukocyte-derived HSP70 peptide complexes were given to 20 CML patients who had cytogenetic or molecular evidence of disease despite ongoing treatment with imatinib (34). In each patient entering this study, HSP70 was purified from the leukapheresed peripheral blood mononuclear cells and administered in eight-week intervals as intradermal injections without immunological adjuvant. The vaccine produced no...

With Bcrablderived Peptide Vaccines

As discussed above, many clinicians still consider allo-geneic stem cell transplantation to be the gold standard for curative therapy in CML by virtue of the long-term survival achieved and the ability of this modality to render the patient BCR ABL negative using PCR-based assays. The importance of the immunologic properties of the graft has received a great amount of attention, with attempts to recapitulate a GvL effect while separating it from the side effects of conventional transplantation regimens undertaken by a number of investigators. The potential to induce and then employ specific antileukemic immune effectors is attractive and has seen realization in the formulation of a vaccine strategy for this disease. Based on the immunogenic evidence of b3a2 peptides-derived translocation, the Memorial Sloan-Kettering Cancer Center (MSKCC) Group initiated studies to evaluate the safety and immunogenicity of a multidose, multivalent BCR ABL breakpoint peptide vaccine in CML patients,...

Vaccination Strategies Based On Dendritic Cells

Problem, including use of low doses of peptide and addition of novel cytokine cocktails during T-cell activation in order to modulate the response. Moreover, synthetic peptides with amino acid substitutions designed to increase their binding efficiency to MHC molecules may be more potent than native peptides for T-cell activation. In the last years, a number of reports demonstrated the efficacy of an antitumor vaccination with peptide-modified DC. Thus, immunization with DC loaded with MHC class I-eluted tumor peptides inhibited tumor progression in mice bearing weakly immunogenic tumors 67 . Also in humans the induction of tumor-directed CTL by peptide- pulsed DC has been shown by several groups 68, 69 . The allelic restriction imposed to selected peptides can partially be bypassed when DC are pulsed with whole tumor proteins. This strategy allows DC to endoge-nously process the proteins and present MHC class I-restricted peptides by cross priming. In addition, MHC class...

Antigenspecific Cancer Vaccination Strategies

Although autologous tumor cell-based vaccines are currently the major form of cancer vaccines tested clinically 74-78 , innovative approaches to antigen-specific vaccinations are underway. The ability to activate immune responses to selected immunodominant tumor epitopes provides for a much greater control in targeting and fine-tuning antitumor immune responses. There is a number of approaches the aims at combining the most potent tumor rejection antigens and the appropriate route or vehicle by which the antigen is delivered to the immune system. A number of strategies have been developed in the past few years in an attempt to optimize cancer vaccines in a rational rather then empirical way. At present, the most widely employed, and the first to be clinically tested, strategy is peptide vaccination. peptide vaccination depends on the loading of empty common HLA alleles on antigen-presenting cells in vivo 79-82 . In poorly-immunogenic murine tumor models, peptides derived from...

Peptide Vaccine Induced Anaphylaxis in the NOD Mouse

The identification of autoantigens in autoimmune diseases such as type 1 diabetes or multiple sclerosis has made peptide immunotherapy possible. In fact, peptide vaccine trials are currently underway in type 1 diabetes for an altered peptide ligand of insulin peptide B 9-23 (20), for GAD peptides, and for heat shock protein 60 (HSP60) (p277) (21). However, in mouse studies of peptide vaccination, anaphylaxis has been reported in diabetes experiments using the B 9-23 peptide (22) and GAD peptides (23) and in multiple sclerosis studies (experimental autoimmune encephalitis) using proteolipid protein (PLP) (139-151) and myelin oligodendrocyte glycoprotein (MOG) (35-55) peptides (24). Even more concerning is the report of systemic hypersensitivity reactions in humans during phase II trials with an altered peptide ligand for myelin basic protein (MBP) (83-99) (25,26), which led to the premature discontinuation of therapy in some patients. More research into peptide-induced anaphylaxis,...

Targeting Tumor Antigens Antigen Specific Vaccines

The ideal breast cancer vaccine would induce broadly reactive immunity to multiple types of breast cancer without causing clinically significant autoimmunity and, most important, be clinically effective. One approach to minimize autoimmunity and enhance specificity of vaccines is to target them to specific protein antigens that are overexpressed on the tumor cells but that have limited distribution in normal tissue. Many breast cancer tumor antigens are also expressed on tumor cells in other epithelial-derived cancers, such as ovarian cancer and colon cancer, and have been targeted in early-phase clinical trials in breast cancer and other solid tumors. In addition to MUC-1, HER2 neu, and telomerase (see subsequently), target antigens include CEA (59,60), cyp1B1 (61), survivin (62,63), and others (Table 1). The HER2 neu antigen is a well-known target of antibody-mediated immunotherapy in breast cancer. The initial demonstration of multiple HLA-A2-binding peptides derived from the HER2...

Cellular Based Vaccines

Vaccines based on whole autologous or allogeneic tumor cells have been combined with strong adjuvants or cytokines, since tumor cells themselves generally stimulate poor antigen presentation (82). Both autologous tumor cells (83-85) and allo-geneic cell lines (86 -88) have been used in clinical trials in breast cancer, with isolated clinical responses reported. Whole tumor cells have also been fused with dendritic cells (89). In murine models, GM-CSF was the most potent cytokine adjuvant for vaccination (90), and GM-CSF-secreting autologous and allogeneic vaccines are currently being evaluated in clinical trials in breast cancer.

Do We Need An Antic pneumoniae Vaccine

A better knowledge of the natural history of C. pneumoniae is required in order to identify the target populations to be vaccinated against C. pneumoniae and to decide whether prophylactic and or therapeutic vaccines would be most desirable. The issue of chronic infection versus repeated infection persistent quiescent infection (which has been unquestionably shown in vitro(3)) or persistent active infection the presence of periods of reactivation and the clinical significance of super infection, need further studies. Whether there are sufficient benefits tojustify children's vaccination seems at present unlikely, since chlamydial respiratory tract infection in children is generally mild. However, transmission of infection to siblings or parents, and the consequences of infection in asthmatic pediatric patients may here be significant parameters to consider.(4) The prevention of arteriosclerosis by blocking C. pneumoniae infection is unlikely to provide a justification for a vaccine...

Shared Tumor Antigen Peptide Vaccines

Another active-specific immunotherapy with potential antitumor effect in CML relies on the use of intracellular proteins other than p210. In fact a number of self proteins are aberrantly overexpressed in CML and other tumor cells while being expressed at low levels in normal lineages and thus may function as targets for directed immunotherapy of residual disease. As in the case of p210, despite the intracellular location of these proteins, short peptides produced by their cellular processing can be presented on the cell surface within the cleft of HLA molecules and in this form they can be recognized by T cells. Several peptide vaccines derived from such proteins have reached the stage of clinical development in CML patients. Proteinase-3-Derived Peptide Vaccines been detected in CML patients and have been implicated in the clearance of malignant cells in patients treated with IFN-a or stem cell transplantation (SCT) (24). Vaccinations of PR1 peptide in Montanide were administered...

SV40 Virus in Early Polio Vaccines

Polio vaccines have been blamed for everything from initiating the AIDS epidemic to being a Western plot to subvert the developing world. Poliovirus vaccines that were used during the late 1950s and early 1960s were contaminated with simian virus 40 (SV40), a monkey virus that came from the monkey cells in which early batches of the vaccine were grown. A survey done in 1961 indicated that about 90 of U.S. citizens younger than 20 years of age (those born between 1941 and 1961) had received at least one immunization with poliovirus vaccine that may have contained SV40 virus.189 It is difficult to determine the average exposure because the titers of live SV40 in different vaccine lots varied from undetectable to high. Most epidemiological studies of populations who were immunized with polio vaccine potentially containing live SV40 during early childhood, which is presumed to be the highest at-risk age group for a lifetime risk of developing an exogenous agent-induced cancer, have failed...

Products From Cell Culture Technology Viral Vaccines

Vaccination for the prevention of infectious diseases has been an effective strategy for many years. Polio vaccine was the first cell culture technology-based vaccine and was produced in cultured monkey kidney cells (7). The cell-based vaccine technology evolved in the last four decades the production of vaccines now utilizes primary cells, human diploid cells, and continuous or even recombinant cell lines. Vaccines against hepatitis B, measles and mumps, rubella, rabies, and FMD had been very effective in preventing life-threatening diseases. New vaccines target human immunodeficiency virus (HIV), herpes simplex virus, respiratory syncytial virus, cytomegal virus (CMV), and influenza, and continue to utilize cell culture technology for production. The latest developments in vaccine development include genetically engineered vaccines and DNA vaccines that will open new frontiers in this field. Development of new vaccines for HIV and cancer is very exciting and these efforts should...

Vaccine for Alzheimers

Alzheimer's disease is a condition where the nerve cells of the brains of elderly people slowly stop working, leading to memory loss, madness, and death. Some scientists think that Alzheimer's is caused by the buildup in the brain of chemicals called amyloid-beta peptides. They are trying to make a vaccine using a kind of vaccine called a DNA vaccine. In this kind of vaccination, DNA is put into body cells. This DNA acts like a recipe for an antibody, which is a substance that helps the body's immune system recognize germs. The antibody made by cells that have received the DNA vaccine are for amyloid-beta peptides. That is, these antibodies cause the body's lymphocytes to attack amyloid-beta peptides and destroy them. Researchers have had good success in mice with DNA vaccine, but are quick to point out that human beings are not simply large mice. What works in mice often does not work in people. It will be years before we can know whether an Alzheimer's vaccine for humans is...

New Therapies 41 Anti Idiotypic Vaccines

Since all major chemotherapeutic treatments in CLL induce good responses but are unable to effect a cure, one of the major questions that needs to be answered is whether there is a place for immunotherapeutic approaches like anti-idiotypic vaccines. Since each B-cell undergoes a unique, characteristic, rearrangement and since malignant B-cell hemopathies are characterized by clonal expansion of a clone displaying a unique rearrangement, idiotype constitutes a privileged tumor antigen. One of the aims of tumor immunotherapy is the induction of CD8 cytotoxic T-lympho-cytes. Although, trials of idiotype vaccination have not been reported in CLL, interesting results were reported in the case of lymphoma patients (93).

Clinical Issues In Vaccination

There are several challenges that affect the development of breast cancer immunotherapies. Molecular typing of breast cancer (108) and genomic identification of breast cancer antigens (109) have made it clear that there are specific biologic types of breast cancer with different levels and patterns of tumor antigen expression. The identification of multiple antigenic targets in breast cancer (Table 1) has required the development of immunologic assays for careful monitoring of antigen-specific immune responses. There is no global assay for assessing immunocompetence, but antigen-specific T-cell responses can now be quantitatively measured with the use of flow cytometry using recombinant tetrameric HLA molecules (110), and plate-based ELISA and Elispot assays for T-cell-dependent cytokine secretion. Whole-cell based vaccines and modulators of immune regulation are more difficult to assess. Delayed-type hypersensitivity to vaccine can be tested in skin-biopsy specimens, and tumor-biopsy...

Selection Of Target Antigens For Antitumor Vaccination

As outlined above, tumor antigens that might serve as potential targets of antigen-specific cancer vaccines are being defined in several cancers. The optimal development of these vaccines requires identification of the most potent rejection antigens. One of the criteria to be considered in selecting antigens for antitumor vaccination is the precursor frequency of antigen-specific tumor-reactive T cells, since the frequency of T cells reactive with particular tumor antigens would bear great relevance to the in vivo immunogenic-ity of such antigen. A second criterion concerns the prevalence and heterogeneity of antigen expression by tumor cells, since identifying target antigens that are expressed by a majority of cancers from different individuals would assist in developing antigen-based therapeutic strategies that could be broadly applied. Moreover, the uniformity of antigen expression in the tumor cell population could also influence the efficacy of the vaccine as the outgrowth of...

Research into a DNA Vaccine for HIV

As of 2006, there was no vaccine to prevent infection by the human immunodeficiency virus (HIV), the virus that causes AIDS. It is important to develop an effective and safe vaccine, since over 25 million people died from AIDS-related causes between 1981 and 2005. Consequently, scientists around the world are working intensively to develop a DNA vaccine and have tested many of these vaccines. Such vaccines are made artificially, so they do not contain any actual HIV viruses. As a result, DNA vaccines cannot infect anyone with HIV. So far, the only side effects associated with experimental HIV DNA vaccines have been minor irritation around the injection area, a low fever, and minor body aches that quickly go away. As with other experimental DNA vaccines, a future HIV vaccine should be safe, inexpensive to make, and not need refrigeration, so that it will be easy to store and give to those who need it.

DNAbased HBV Vaccines

Experimental DNA vaccines stimulate both T- and B-cell immune responses to HBV, and may be more effective in the treatment of chronic hepatitis B than peptide vaccines (63). Trials conducted on transgenic mice that express the HBV surface gene showed that vaccination with plasmid DNA resulted in decreased production of HBsAg. The results of pilot clinical trials are eagerly awaited. Cytotoxic T-cells play an important role in the clearance of intracellular virus. A vaccine incorporating a cytotoxic T-lymphocyte epitope, derived from hepatitis B core protein, was evaluated in a pilot clinical study (64). Although the vaccine induced a cytotoxic T-lymphocyte response in some patients, it was not sufficient to achieve virus clearance. In addition, this vaccine appeared to be less effective in patients who are in the immune-tolerant phase of HBV infection.

Vaccination Strategies

Current vaccination strategies in the United States call for screening all pregnant women for HBsAg, and rapid immunization with both vaccine and hepatitis B immunoglobulins of the neonates of those women found to be HBsAg-positive. Other infants, children, and adolescents through 18 yr of age, and high-risk groups are also candidates for HBV vaccine. High-risk groups are generally defined as individuals with more than one sexual partner in a 6-mo period, and homosexual or bisexual males. Attendees at sexually transmitted disease clinics or public health clinics, and adolescents living in areas with a high frequency of teenage pregnancy, should be vaccinated. Intimate or household contacts of individuals who are HBsAg-positive also are vaccine candidates. Illicit injection drug users and patients with bleeding disorders, who are likely to receive nonrecombinant clotting factor preparations, should receive HBV vaccine. Patients with chronic renal failure are routinely vaccinated, and...

S andpreS HBV Vaccines

The basis for peptide vaccine therapy in chronic hepatitis B is to stimulate immune response to HBV. Pre-S Ags have been shown to be more immunogenic than the S antigen (HBsAg), and may stimulate both Tand B-cell response. In one study (62), 170 patients were randomized to receive GenHevac (preS2 S antigen-containing vaccine), Recombivax (S antigen-containing vaccine) or no treatment. Most patients were subsequently treated with IFN-a after completion of the vaccine schedule. The data, available only in 40 patients, showed that clearance of HBV DNA and HBeAg were seen in 5 17 patients vaccinated with GenHevac. Significant decrease in HBV DNA level was seen in 2 10 patients vaccinated with Recombivax. HBV DNA clearance was seen in 1 13 controls. Because of the design of the study, which included IFN- a treatment after the end of vaccination schedule, and the high dropout rate, it is not possible to ascertain the efficacy and durability of the response to the vaccines per se....

HBV Vaccines and Regimens

Plasma-derived vaccines comprise about 80 of worldwide HBV vaccine production, but are no longer available in the United States. Recombinant HBV vaccines were approved for use in the United States in 1986 and 1989. The two commercially available vaccines are produced by cloning the gene encoding the HBsAg, through use of a plas-mid vector inserted into common baker's yeast. The yeast-derived HBsAg particles induce immunity by stimulating the endogenous production of neutralizing antibody to HBsAg (anti-HBs). Seroprotection is thought to be achieved when anti-HBs levels are 10 mlU mL or higher. Antibody to the hepatitis B core antigen (anti-HBc) is not induced by the recombinant HBV vaccines. Rarely, transiently positive tests for HBsAg in serum may be found within 24 h following vaccine administration. The HBV vaccines are highly immunogenic, and are conventionally given in a three-dose schedule utilizing a deltoid injection site, or, in infants, the anterolateral muscle of the thigh....

Candidates for HCV Vaccine

Appropriate candidates for a HCV vaccine may include newly identified injection drug users or intranasal cocaine users, renal failure patients at risk for hemodialysis, patients with blood-clotting disorders, and other recipients of multiple blood products, the sex partners of HCV-infected individuals, and possibly sex workers. Patients with other chronic liver diseases would be targeted, as well. Although the prevalence of infection appears to be low in health care personnel, those regularly exposed to blood and body fluids might be considered for immunization. If early administration, e.g., shortly after birth, of a HCV vaccine to the neonates of infected women could protect the neonates, then identification pre-delivery of pregnant HCV-infected women would become critically important. Because vaccine delivery to injection drug users early in their careers remains problematic, it seems likely that a targeted approach to high-risk individuals is likely to fail. If this concept is...

CD137CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination

Immunotherapy has potential for chronic and latent viral infections. Therapeutic vaccination and adoptive T-cell transfer are the strategies that are being explored for HIV and chronic viral hepatitis. Mice lacking CD137 or CD137 ligand show defects in CD8 T cell responses against viruses (DeBenedette et al., A pioneering study (Halstead et al., 2002) demonstrated increased CTL responses against experimental influenza. In vivo CD137 stimulation with an agonistic monoclonal antibody enhanced the primary CD8+ T cell response to influenza type A viral infection in mice. Stimulation of CD137 increased the absolute number of CD8+ T cells to influenza epitopes in the lungs of infected animals, preferentially expanding CD8+ T cells that recognized nondominant epitopes and greatly enhancing direct ex vivo cytotoxicity. The studies confirmed that the CD137 costimulatory pathway could operate independently from CD28 (Halstead et al., 2002). The effects enhancing memory to a broadened series of...

Active Specific Immunotherapy Vaccines

As a general concept a therapeutic antitumor vaccine refers to the subcutaneous administration of a tumor-specific antigen with the intent to induce an active and possibly long-lasting humoral and or cellular immune response able to eliminate tumor cells harboring the putative antigen. Many years of disappointing clinical results with antitumor vaccines against different types of advanced solid tumors has taught tumor immunologists that the best setting for effective immunotherapy is the situation of MRD (10). In CML, like in other tumors, the ideal vaccine candidate would be an antigen expressed only in tumor cells, but common to all patients. It should be highly immunogenic and should be essential for tumor cell survival, and thus not susceptible to mutation or deletion. Several CML antigens have been identified as potential targets for an anti-CML vaccine strategy (Fig. 1), and different approaches at different stages of development are now under evaluation for CML patients (Table...

Vaccines

Several vaccines are currently in clinical trials for follicular NHL. Most of these are directed against the idio-type of the hypervariable region of the immunoglobu-lin light chain. Interest in this approach has been stimulated by a number of nonrandomized studies, such as one from Stanford in which 49 of patients with follicular NHL reacted to their own idiotype conjugated to keyhole limpet hemocyanin (KLH) by exhibiting a cellular and humoral immune response. Those patients capable of mounting such a response had a time to tumor progression of 7.9 years compared to 1.3 years for those who could not.95 The results of the three randomized trials will determine if there is clinical benefit from this approach.

Tumor Vaccines

Tumor vaccines are an active immunotherapy in which the host is induced to generate an immune response against autologous tumor cells. The different types of vaccines are quite variable and include those directed at known tumor-specific antigens, such as the idiotype vaccines and modified tumor cellular vaccines that attempt to enhance immunogenicity by introducing granuloctye macrophage colony-stimulating factor or other ligands, which improve or induce tumor antigen presentation into tumor cells. In addition, the use of primed antigen presenting cells, such as dendritic cells, to improve the immune response to the desired tumor antigens is also being explored. target for immunotherapy. The first clinical trial of idiotype vaccines in patients with follicular lymphoma was conducted by Dr. Levy's group at Stanford.7778 Thirty-two patients with follicular lymphoma in first remission were treated with autologous purified Id protein chemically linked to kehale impel (KLH) as an...

Vaccine Efficacy

Traditionally, in etiological and cancer prevention studies, the measurable endpoint to determine efficacy of an intervention has been the incidence of cancer itself. But as some cancers take a long time to develop and are not common in a given population, trials with an endpoint of invasive cancer can be prohibitively large and lengthy. In the case of cervical cancer, a disease that can be prevented through proper detection and treatment, a study endpoint of cancer can be ethically impracticable. The US Food and Drug administration Vaccine Advisory Committee has recommended using CIN2 3 as a surrogate marker for cervical cancer in HPV vaccine trials, as this lesion is the intermediate precursor to cervical cancer (Pratt et al. 2001). Since persistent infection with the same high-risk type is considered a predictor for high-grade cervical dysplasia and cancer, it might be a useful surrogate in future vaccine efficacy studies. Indeed, if vaccines prove to be effective against transient...

Vaccine Development

Over the last 20 years, extensive research has focused on vaccine development, but so far the outlook for vaccines is less optimistic than for drug discovery. An effective malaria vaccine must induce a protective immune response equivalent to or better than that provided by natural immunity. Indeed, when an adult who acquired natural immunity returns to his or her endemic area after a few months, he has usually lost his protective immunity and become sick. For this reason, an effective malaria vaccine requires new methods of maximizing the longevity of the protective immune response. The winning vaccine will possess multiantigenic determinants with multistage expression. The most promising antigens under evaluation for use in vaccine development against the erythrocytic stage are targeted at the invasive step of the malaria parasite (e.g., merozoite surface proteins, erythrocyte binding antigens, and rhoptry proteins). Interestingly, all of these potential targets have similar...

DNA Vaccination

This technique is currently being explored as a potential strategy for treating CLL and other B-cell malignancies. For patients with B-cell tumors, the immunoglobulin idiotype expressed by the neoplastic clone provides a defined tumor-specific target antigen. However, the immunoglobulin idiotype is poorly immunogenic, especially in patients with CLL. Fusion of a gene encoding a fragment of tetanus toxin with the gene encoding the idiotype can enhance the immune response to such weak tumor-specific antigens. DNA fusion vaccines containing genes that encode immune-enhancing factors can also augment the immune response to such antigens (38-40).

Vaccination

Vaccination is another promising area for inducing antimyeloma immunity. T-cell recognition of myeloma is suggested by the restricted usage of Va and Vp segments in the peripheral blood82 the presence of activated Id-reactive CD8+ cells83 as well as CD4+ cells84 the growth of T-cell clones by stimulation with IL-2 and F(ab')2 fragments derived from autologous Id85 as well as the production of cytokines such as interferon (IFN- ), interleukin 2 (IL-2), and IL-4 after stimulation with autologous Id.86 87 The Id-reactive population includes T cells that are not MHC restricted and that recognize conformational epitopes on Ig, as well as CD4+ and CD8+ cells, which recognize Id-derived peptides in association with MHC Class I and Class II molecules.88 The Id-reactive T-cell expansion has been correlated with tumor load,83,87 and a shift from type I to type II T-cell response has been correlated with disease progression.85 It has been shown that vaccination with Id67,89 or the use of...

Prophylactic Vaccine

In general, prophylactic vaccines induce the generation of neutralizing antibody to the pathogen and thus prevent disease on subsequent exposure. Studies exploiting natural papillomavirus infections in the dog, rabbit, and cow, together with HPV1 and HPV11 infections in humans (all situations in which adequate amounts of virus could be obtained), showed clearly that there were serum responses to viral capsid proteins in individuals who were or had been infected (Stanley 1997). In the animal models, seropositive individuals were resistant to subsequent viral challenge. Neutralizing antibody, directed to determinants on the viral capsid L1 protein, was generated in these individuals (Stanley 2006a). These observations suggested that a vaccine generating such responses must contain L1 protein in the correctly folded, tertiary or native form. Technically, this was very difficult, but a major experimental breakthrough showed that the L1 protein, when expressed by vectors such as...

Techniques Of Discovery

Express human genes, for example, in microbial, Escherichia coli or yeast, cells so that they manufacture proteins that medicinal chemists have not been able to synthesise they also produce hormones and autacoids in commercial amounts (such as insulin and growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and immune antibodies). Transgenic animals (that breed true for the gene) are also being developed as models for human disease as well as for production of medicines.

The Current and Evolving Regulatory Environment

In the United States, the USA PATRIOT Act of 2001 and the Bioterrorism Preparedness and Response Act of 2002 already establish the statutory and regulatory basis for protecting biological materials from inadvertent misuse. Once fully implemented, the mandated registration for possession of certain pathogens (the select agents ), designation of restricted individuals who may not possess select agents, and a regulatory system for the physical security of the most dangerous pathogens within the United States will provide a useful accounting of domestic laboratories engaged in legitimate research and some reduction in the risk of pathogens acquired from designated facilities falling into the hands of terrorists. The Committee stresses that implementation of current legislation must not be overly restrictive given the critical role that the development of effective vaccines, diagnostics, therapeutics, and detection systems, along with a responsive public health system, will play in...

Bioassayand Standardisation

Biological assay (bioassay) is the process by which the activity of a substance (identified or unidentified) is measured on living material e.g. contraction of bronchial, uterine or vascular muscle. It is used only when chemical or physical methods are not practicable as in the case of a mixture of active substances, or of an incompletely purified preparation, or where no chemical method has been developed. The activity of a preparation is expressed relative to that of a standard preparation of the same substance. Biological standardisation is a specialised form of bioassay. It involves matching of material of unknown potency with an International or National Standard with the objective of providing a preparation for use in therapeutics and research. The results are expressed as units of a substance rather than its weight, e.g. insulin, vaccines.

Ventricular Tachycardia Fibrillation and Sudden Death

Although sudden death is mentioned in the Bible, the first studies linking sudden death to coronary artery disease date from the eighteenth century. In 1799, Caleb Parry quoted a letter from a good friend, Edward Jenner, the discoverer of smallpox vaccination. Jenner described an autopsy he had done

Physiologically Active Substances A

Ethylene is effective when given 5-30 days before irradiation (202). Other inhibitors of mitosis, however, can enhance survival these include demecolcine (Colcemid), sodium ar-senite, epinephrine, cortisone, and typhoid paratyphoid vaccine (203). Tranquilizers and other psychotropic drugs possess only moderate radioprotective activities. These compounds probably are active by depression of whole-body metabolism through diminished oxygen uptake (35). 1.4.8 Metabolites and Naturally Occurring Compounds. A variety of compounds in these categories have been examined for radiation protection, but few effective protectants have been found. Some polysaccharides, such as dextran (209), those extracted from typhoid and proteus organisms (210), and a lipopoly-saccharidefromS. abortus (211), provide some protection for mice, possibly by inducing phagocytosis. Bacterial endotoxins, which are lipopolysaccarides of molecular weight around 1,000,000, show relatively good protective properties in...

Sexually Transmitted Infections

Hepatitis B virus (HBV) can be acquired through consensual and nonconsensual sexual activity (210). Therefore, HBV vaccine should be offered to all adult victims of sexual assault (202). In children and young people, a risk benefit analysis will inform the decision regarding whether the vaccine should be offered. It is not known how soon after the sexual assault the HBV vaccine needs to be given to have an effect. However, because of the long incubation period an accelerated course of the vaccine (0, 1, and 2 months or 0, 1, and 6 months) may be efficacious if is initiated within 3 weeks of the exposure (202).

Early Days of Cell Culture Technology First Products

Utilization of cultured cells for the production of viral vaccines was the first application of cell culture technology. Viruses for vaccine production need living cells to propagate. Embryonic chicken in eggs traditionally was used for vaccine production. Due to increased demand, alternative methods were sought and cell culture technology was the answer. The production of polio vaccine using cells grown in culture started in 1954 (4). The cells were primary monkey kidney cells grown on surfaces (attachment dependent cells). A similar development took place for the vaccine against foot-and-mouth disease for veterinary use. Large-scale vaccine production for FMD virus was a major activity 36 years ago. Increased demand and process economics required more effective and scalable processes. Baby hamster kidney (BHK) cells were adopted for this process and FMD vaccine could then be produced at a 5000 L scale in suspension bioreactors. The medium used for this production was Eagle's medium...

Lmmunotherapy Using Dendritic Cells

Recently, DC have been used in numerous clinical trials for the treatment of cancer. Immunization with DC is not toxic in either healthy subjects or cancer patients no dose-limiting toxicity has been observed (79). The induction of tumor-specific T-cell responses has been detected in patients that have received DC immunotherapy. Several clinical trials are currently in progress investigating the safety and efficacy of immunotherapy of cancer with DC. Ex viuo incubation of DC with a source of tumor antigens is necessary to load tumor-derived antigenic epitopes on DC. Large numbers of DC generated ex vivo can be manipulated to enhance tumor antigen presentation and then re-administered to the patient to study the efficacy of DC immunotherapy. DC have been shown to induce strong anti-tumor immune responses both in uitro and in viuo. Early vaccination protocols involved DC pulsed with synthetic HLA-binding peptides. Since then, many other strategies involving DC have been investigated,...

Conclusion and Future Directions

HPV causes the most common viral infection of the reproductive tract worldwide. However, the infection is often transient and self-limited. Several studies have suggested that HPV infection and cervical dysplasia can be prevented by HPV L1 VLP vaccines. The licensure of a vaccine against HPV represents a major public health advance against cervical cancer and other less common cancers including those of the anus, vagina, and vulva. Much still needs to be investigated regarding the local immune responses to the vaccine in the lower genital tract, longevity of immune responses, and alternative delivery routes such as intravaginal, intranasal, and oral administration. The epidemiology of cervical cancer highlights the need to provide HPV vaccines to persons who may never or rarely be screened, as well as to improve cervical cancer prevention programs so that they will reach the women with the highest risk of disease. However, it will be far easier to recommend routine vaccination than to...

Chemoprophylaxis Of Malaria

Geographically variable plasmodial drug resistance has become a major factor in malaria. The World Health Organization gives advice in its annually revised booklet, Vaccination Certificate Requirements and Health Advice for International Travel and national bodies publish advice (e.g. British National Formulary) that applies particularly to their own residents. These or other appropriate sources ought to be consulted before specific advice is given. The following general principles apply Naturally acquired immunity offers the most reliable protection for people living permanently in endemic areas (below). Repeated attacks of malaria confer partial immunity and the disease often becomes no more than an occasional inconvenience. Vaccines to confer active immunity are under development.

Lifespan And Maximum Survival

From the perspective of those who study aging, there is an important distinction made between median (life expectancy) and maximum life span. Over the past several decades, with the advent of modern sanitation, refrigeration and other public health measures including vaccination and antibiotics, there has been a dramatic increase in median survival 10. Early deaths have been diminished and more individuals are reaching old age. In the United States today, life expectancy now approaches 80 years 11. Median survival is what concerns public health officials and health care providers but for those studying the biology of aging, it is maximum survival that is the focus of greatest attention. It is worthwhile to note that it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about ten years would be added to the average life span, yet there would be no change in maximum life span 12.

Immune Recognition Of Tumor Stress Proteins

The observations under items (3) and (4) have strong implications for vaccine development against cancer, because they suggest that active immunization with stress protein preparations from tumors can elicit tumor-specific T-cell responses and immunologically mediated tumor regressions. This will be reviewed and discussed in the subsequent part of the article.

Other Treatment Strategies And Future Directions

Nonmyeloablative allogeneic stem cell bone marrow transplantation has been explored, with encouraging responses and reduced toxicity, enabling older patients to undergo this treatment modality. New biological agents such as the bcl-2 antisense and the proteasome inhibitor PS-341 are in the early phases of clinical trials, and treatment with autologous DNA vaccine is also being investigated. Details regarding these treatment strategies are discussed in other chapters of this textbook.

Future Considerations

Cious.67 Other intriguing possibilities include the use of methods to enhance GvL effect, such as dendritic cell vaccines. DLI, occasionally used successfully in the setting of relapse after allo SCT in NHL, may be associated with the development of severe and fatal GvHD. Newer uses of DLI include preemptive infusion in patients at high risk for relapse (due to aggressive disease or because the allograft was T-cell depleted), or use of selective, i.e., CD8+ T-cell depleted, DLIs in an attempt to provide GvL effect without GvHD.68-70 As discussed above, a number of investigators are using tandem auto SCT followed by allo SCT approaches. Recently, several groups have begun using novel conditioning regimens incorporating agents such as pen-tostatin71 or the combination of pentostatin and extracorporeal photopheresis (ECP).72 Chin et al.72 reported in preliminary fashion their allo SCT reduced-intensity regimen combining lower dose TBI, pentostatin, and ECP in poor-risk patients. A total...

Approach To Suspected Meningitis

Bacterial meningitis is the most common pus-forming intracranial infection, with an incidence of 2.5 per lO.OOO persons. The microbiology of the disease has changed somewhat since the introduction of the Haemophilus influenza type B vaccine in the 1980s. Now Streptococcus pneumoniae is the most common bacterial isolate, with Neisseria meningitidis a close second.

Management in Custody

It is not possible to tell if a detainee is a carrier. Nevertheless, the risk of acquiring infection even from an infected and sick individual is low, unless the individual has carried out mouth-to-mouth resuscitation. Any staff member who believes he or she has been placed at risk should report to the occupational health department (or equivalent) or the nearest emergency department at the earliest opportunity for vaccination. If the detainee has performed mouth-to-mouth resuscitation, prophylactic antibiotics should be given before receiving vaccination. Rifampicin, ciprofloxacin, and ceftriaxone can be used however, ciprofloxacin has numerous advantages (66). Only a single dose of 500 mg (adults and children older than 12 years) is needed and has fewer side effects and contraindications than rifampicin. Ceftriaxone has to be given by injection and is therefore best avoided in the custodial setting. If the staff member is pregnant, advice should be sought from a consultant...

Epidemiology and Prevalence

In the United Kingdom, there has been a gradual decrease in the number of reported cases from 1990 to 2000 (83,84). This results from, in part, improved standards of living and the introduction of an effective vaccine. The highest incidence occurs in the 15- to 34-year-old age group. Approximately 25 of people older than 40 years have natural immunity, leaving the remainder susceptible to infection (85).

Dendritic Cell lmmunotherapy Approaches for Undefined Tumor Antigens

An important issue in optimizing DC vaccines is choosing an ideal tumor antigen for DC loading Tumor cell lysates, apoptotic tumor bodies, and tumor cells can be used as immunogens in E)C cancer therapy for the development of anti-tumor strategies. For several tumor types, antigenic epitopes are unknown. In contrast to peptide immunotherapy, using tumor-derived products bypasses the need to consider HLA haplotypes and the identification of specific tumor-derived antigens. Several of these treatment modalities will now be reviewed, which demonstrate specific anti-tu-rnr responses against tumors with undefined tumor antigens. 3.4.2 Tumor Lysates. Compared with vaccination approaches directed against a single tumor antigen, tumor cell lysates contain an array of tumor-derived antigens that have the potential of inducing broad T-cell responses against multiple antigens expressed by tumor cells, either previously identified antigens or unknown tumor-derived antigens. Although many vaccines...

Prophylaxis and Treatment

Contacts of HAV should receive HAV vaccine (e.g., Havrix Monodose or Avaxim) if they have not been previously immunized or had disease. Human normal immunoglobulin (HNIG), 500 mg, deep intramuscular in gluteal muscle should be used in the following circumstances Staff at higher risk of coming in to contact with HAV should consider being vaccinated before exposure. Two doses of vaccine given 6-12 months apart give at least 10 years of protection.

Introduction of Monoclonal Antibodies Into Clinical Practice

Despite the theoretical advantages of using anti-Id MAb, identification of an individual patient's Id protein sequence and generation of an individualized anti-Id MAb are not feasible on a large scale with current available technology. Id vaccines may be an alternative approach if the immune deficiency of CLL can be overcome to allow generation of a primary and persistent secondary immune response. Id vaccines, which have shown promise in B-cell NHL, are now entering clinical trials in CLL. Development of monoclonal antibodies has become focused on the use of antigens specific for tumors, as opposed to patient-specific antigens, to allow broad therapeutic applicability of each monoclonal antibody. Monoclonal antibodies generated against several such antigens in CLL are reviewed in this chapter.

Effects of CD137 Engagement on CD8 T Cells in vivo

Two initial studies in 1997 demonstrated that engagement of CD137 in vivo by CD137 agonistic mAb enhances CD8 T cell proliferation and IFN-gamma production, therefore promoting acute graft versus host (GVH) disease, accelerating the cardiac and skin allograft rejection and tumor rejection (Melero et al., 1997 Shuford et al., 1997). In consistent with these findings, Cooper et al. showed that in vivo blockade of CD137 by CD137-Fc fusion protein inhibits CD8+ T cell expansion in the primary response to ovalbumin protein in adjuvant (Cooper et al., 2002). When adoptive transferred T cells are CFSE-labeled to trace cell division, administration of CD137-Fc in vivo significantly inhibits T cell division, demonstrating that CD137 functions to regulate CD8+ T cell clonal expansion by enhancing proliferation. In a tumor model, Ito et al. (2004) found that administration of CD137 mAb can enhance antitumor efficiency of dendritic cell-based vaccine. When CFSE-labeled OT-1 cells were adoptively...

The Role Of Nanotechnology In Drug Delivery

Other transdermal applications include dendrimers which are extensively used to deliver drugs, vaccines, and chemotherapeutic agents for cancer therapy 18 . Some of the dendrimer-based bionano applications include gene delivery, targeted cancer therapy, in vivo diagnoses (MRI), antiinfective agent delivery, vaccine and peptide delivery and drug delivery through oral and transdermal routes and ocular applications 18 .

Histologic Transformation Of Follicular Lymphoma

After decades of clinical research using various combinations of nonspecific cytotoxic drugs, there is now a wealth of new approaches for patients with follicular NHL. The availability of an expanding menu of novel targeted agents provides great promise for therapeutic advances. These include monoclonal antibodies such as rituximab, radioimmunotherapeutics, anti-idiotype vaccines, antisense oligonucleotides, and proteasome inhibitors. Clearly, higher complete and overall response rates are achieved with antibody-chemotherapy combinations than with chemotherapy alone however, whether an eventual prolongation in survival will be achieved remains to be demonstrated by longer follow-up. As there is still no consensus as to the optimal initial therapy, a clinical trial remains the preferred option (Figure 53.1). The potential for cure will result from the rational development of multiple targeted agents with individualized treatment selection based on specific molecular and biologic...

Mechanisms Of Immunogenicity Of Tumor Stress Protein Preparations

Another function of tumor stress protein preparations, which augments the specific immune responses and may be responsible for the extraordinary effec-tivity of tumor-derived HSP vaccines is the activation of innate immunity. NK cells are essential in addition to T cells for the gp96-induced therapeutic immunity against tumors in early phases of tumor growth and metastasis 45 . This corresponds to the observation of Multhoff et. al. 16, 29 that NK cells can recognize HSP 70 directly on the surface of human tumor cells. It is still unclear, as to whether, or not, yS-T cells also contribute to stress protein-induced tumor immunity. The demonstration that yS-T cells or CD4 CD8 negative T cells can recognize HSP 70 on the cell surface of tumor cells, presumably in association with specific tumor antigens 32, 33 , points to this possibility. In addition to the activation of cytotoxic effector cells of the innate immune system, preliminary data suggest that gp96 preparations primarily...

Monoclonal Antibodies

Monoclonal antibodies may be engineered to combine the antibody with a toxin (immuno-toxins) or a radioactive isotope (radioimmunoconjugates) or may contain a second specificity (bispecific antibodies) (Table 2). For example, it is possible to conjugate an antibody with specificity to B-cell lymphomas with an antibody against CD3, which binds to and activates normal T-cells, in order to enhance T-cell-mediated lysis of the lymphoma cell. One such example of a bispecific antibody contains anti-CD3 and anti-CD19 specificity. Monoclonal antibodies raised against the immunoglobulin idiotype on a B-cell lymphoma represents another therapeutic strategy, which was first reported in 1982 by Levy et al. (34). More recently, idiotype vaccines used to induce a polyclonal host antibody response against the malignant clone have shown promise as an effective treatment for minimal residual disease in follicular lymphomas.

Advisors and Contributors

1953 Jonas Salk begins testing a polio vaccine comprised of a mixture of killed viruses. 1955 National Institutes of Health organizes a Division of Bio-logics Control within the U.S. Food and Drug Administration (FDA), following deaths from a faulty polio vaccine. 1965 Anthrax vaccine adsorbed (AVA), is approved for use in the United States. 2002 The planned destruction of stocks of smallpox-causing variola virus at the two remaining depositories in the United States and Russia is delayed over fears that large-scale production of vaccine might be needed in the event of a bioterrorist action.

Scientific Foundations

When influenza vaccines are not available, anti-viral drugs such as Tamiflu usually shorten the course of the disease. SPL Photo Researchers, Inc. Most vaccines work by putting antigens in the body, sometimes as part of dead or weakened pathogens. The antigens do not make us sick, but they do turn some naive lymphocytes into active cells and then memory cells. When living pathogens tagged with those antigens enter the body smallpox or polio viruses, for example the body attacks them at once with active lymphocytes.

Graftversusmyeloma Effect And Donor Lymphocyte Infusion

Similar to chronic myelogenous leukemia, there are several lines of indirect evidence supporting the existence of an alloimmune antimyeloma response, or GvM effect. This evidence includes the observation that molecular remissions are more common after allo-geneic transplantation than after autologous transplantation in patients with myeloma.16 In addition, the relapse rates are lower after allogeneic transplant compared with autologous transplantation. Some patients with persistent evidence of disease after allo-geneic transplantation gradually achieve complete remission without further therapy. Finally, it has been shown that vaccination of the allogeneic donor against the patient's idiotypic protein can facilitate transfer of donor immunity to myeloma at the time of transplantation.37

Adeno Associated Viruses

Another unfavorable feature is that AAV vectors apparently do not infect lymphocytes or CLL cells efficiently, making it necessary to consider ex vivo transduction strategies that use AAV vectors at high concentration. Nonetheless, AAV vectors can efficiently transfer genes encoding antigens to cells in skin or muscle, allowing for their potential use as vaccines encoding tumor-associated antigens.

Initiating a chemostat culture

Chemostat Culture

5.7 GROWTH OF HUMAN DIPLOID FIBROBLASTS FOR VACCINE PRODUCTION MULTIPLATE CULTURE For many years human diploid cells have been utilized for the large-scale manufacture of viral vaccines. With the most recent developments in biotechnology, these cells are also capable of producing a variety of protein products. The history of establishment, growth and storage of human diploid cell lines has been extensively investigated and well documented. The absence of spontaneous transformation and adventitious viruses, a stable diploid karyotype and support of growth of a wide range of viruses are some of the reasons why these cells have been the substrate of choice for the production of biologicals. The growth of these cell lines has been greatly facilitated by the development of microcarriers. In microcarrier cultures, cells grow as monolayers on the surface of small spherical beads that are suspended in a suitable medium and in a vessel with constant stirring. The advantage of using this type...

Pathogenesis And Epidemiology 31 Tuberculosis

Control of the disease has been achieved in part through mass vaccination with BCG (the bacillus of Calmette and Guerin, an attenuated strain ofM. tuberculosisbovis), but above all through correct application of active che-motherapeuticagents. Chemotherapeutic treatment now available enables to stop the propagation of the disease in a high percentage of cases, by killing the pathogenic bacilli, thus permitting the organism to repair or to confine the pathological alterations. Another important consequence of chemotherapeutic treat The majority of people exposed to leprosy will not develop it. Those who develop it, after an incubation period that can range from 1 to 40 years (usually 5-7 years), may have only single lesion (indeterminate leprosy) that is often self-healing or may progress to the pauc-ibacillary or multibacillary stages. The progression and evolution of the infection is influenced by many factors socioeconomic status, immune status of the host, genetic factors, and...

CerbB2 as a predictive factor for response to trastuzumab

Studies of trastuzumab in the preoperative setting with paclitaxel or docetaxel demonstrated high response rates of 75 (78,80). MD Anderson Cancer Center investigators have recently demonstrated that the addition of trastuzumab to preoperative anthracycline and taxane-based chemotherapy was associated with a marked increase in pathological complete response (81). The role of adjuvant trastuzumab with or following systemic chemotherapy is under extensive investigation. Recent results from large cooperative group clinical trials designed to evaluate the efficacy and toxicity of trastuzumab in the adjuvant setting were recently presented in abstract form. The addition of trastuzumab to standard adjuvant systemic therapy provided a substantial improvement in DFS and OS. Importantly, investigators have found discrepancies in evaluation of c-erb-B2 testing of patients enrolled in adjuvant randomized clinical trials of chemotherapy with or without trastuzumab compared to a central laboratory...

Association Vs Causation In Environmental Epidemiology

This raises questions regarding the value of such information for any purpose other than after-the-fact epidemiological analysis, which is not useful for the commander in the field who has the responsibility to complete the mission managing competing risks. Commanders are currently trained to manage risk in accordance with FM 100-14, Risk Management, which applies a probability severity of health outcome matrix to hazards69 (Figure 9.3). Obvious catastrophic events such as a release of highly toxic materials would have severe health risks, although the probability of such a release can only be estimated (Figure 9.4). However, since the most profound preventive action is avoidance, troop locations can be selected with regard to proximity and plume direction from industrial facilities. With respect to exposure to low ambient levels of chemicals, health effects may be delayed or produce little obvious and measurable impact on the immediate mission, but the probability of...

Immunogenicity An Overview

Ies by Prehn and Main 7 in the 1950s. These and other investigators demonstrated that tumor-specific immunity could be induced in syngeneic mice by inactivating parental tumor cells through either irradiation or surgical resection 8-12 , Mice vaccinated by inactivated autologous tumor cells were found to acquire the ability to reject a subsequent challenge of live parental tumor cells, in contrast to naive animals which succumbed to a similar challenge. An interesting aspect of this mode of vaccination was its exquisite specificity. Protection was not reactive to distinct tumors, including those which were generated in identical littermates by the application of the same carcinogens. The vaccination challenge experiments were used to classify murine tumors on the basis of their im-munogenicity. An important finding that emerged from such classification was that tumors which exhibited immunogenicity in a vaccination challenge setting were found to be those induced by identifiable...

The Arrival of Agonistic AntiCD137 Monoclonal Antibodies

Current tumor immunotherapy includes a series of approaches that intend to destroy malignant tissue by means of the cell destructive armamentarium with which the immune system is endowed. Priming and enhancing the cellular immune response against cancer cells or critical components of the tumor stroma is a difficult endeavor, but recent advances have achieved complete regressions of established transplantable rodent malignancies. Among these experimentally successful approaches we can list (i) vaccinations with dendritic cells pulsed with tumor antigens and other vaccine formulations (Banchereau and Palucka, 2005) (ii) adoptive transfer of in vitro-preactivated lymphocytes into a tumor bearing host in whom lymphopenia has been induced (Dudley et al., 2002) (iii) systemic or local treatment with cytokines, including gene therapy approaches, that augment the cellular immune response (Murphy et al., 1996, 2005) (iv) transfection of costimulatory molecules for T cells into cancer cells...

Sexual Transmission of HBV and HCV

In the affirmative, advice is appropriate about changing behavior and the use of condoms to protect their partners and themselves. Vaccination against HBV should be undertaken in those susceptibles engaged in high-risk sex, and, if the individual is a male homosexual, vaccination against HAV is also reasonable. HBV vaccine should also be offered to as many of the sexual contacts of individuals found to be HBsAg-posi-tive as logistically possible. Potential strategies for reducing sexual transmission are listed in Table 2. Long-term and monogamous sexual partners of HBV- or HCV-infected individuals should be tested for evidence of infection. If the index case has HBV, vaccination is recommended for the susceptible sexual partner. For the sexual partner of the index case with HCV, recommendations have been more equivocal and mostly limited to testing the partner for evidence of infection and providing information about the potential risks, so that an educated decision about the use of...

Prophylaxis And Therapy

Patients with chronic GVHD should receive prophylactic antibiotic therapy directed against encapsulated organisms as long as immunosuppressive treatment is being administered the regimen should be selected based upon local resistance patterns of S. pneumoniae and H. influenzae.2 The 23-valent pneumococcal polysaccharide vaccine should be administered 12-24 months after HSCT and HiB conjugate vaccine should be given at 12, 14, and 24 months as well.2 Patients with hypogammaglobulinemia may require replacement therapy if they experience recurrent infections with encapsulated organisms, or at the time of a serious first episode.

Nanosomes and Polymersomes

To increase the safety and efficacy of gene therapy and genetically derived vaccines, efforts are underway to target DNA complexes into hepatocytes and macrophages. Undoubtedly polymersomes would play a significant role in such applications. Small-sized micelles in the nano domain also classify under nanosomes and are used to develop agents for y-scintigraphy, magnetic resonance imaging (MRI), and computed tomography (CT) 40 . Liposomes are another integral member of the nanosome family they are increasingly used in drug delivery applications. A fairly detailed layout on liposomes, their synthesis, and applications is discussed in Chapter 3 and Chapter 5.

Immunoprophylaxis Of Hepatitis B

Hepatitis B virus (HBV) infection is the most common vaccine-preventable liver disease in the world. Over 300 million are chronically infected, and as many as 1 million deaths are attributed to the sequelae of this infection annually. The extraordinary protective efficacy of HBV vaccines, combined with their ability to provide prolonged protection in most individuals, strongly suggests that, despite concerns about the emergence of mutant HBV strains, universal use of the vaccines will eventually markedly reduce, if not eliminate, this infection. Although routine infant immunization against HBV has been adopted in many nations,

Federal Oversight of Tissue Banking

The FDA established a special office, the Human Tissue Program within the Office for Blood Research and Review of the Center for Biologics Evaluation and Research (CBER) to monitor tissue banking activities. CBER is one of the FDA centers responsible for regulating biologic products such as therapeutics, vaccines, blood, and blood products. The mission of the Human Tissue Program, established in 1995,

Patent Law and Biotech

The application of patent law to the human genome is a source of fierce national and international debate, a situation highlighted by James Watson's resignation when Craig Venter and the NIH, under Bernadine Healy, decided to file patent applications for DNA sequences. Proponents of patenting DNA, including most U.S. biotech corporations, contend that companies will not invest money in genomic research without the protection afforded by patents. The arguments against patenting DNA sequences are predominantly from international organizations. They are concerned that gene patents are stifling scientific research and slowing economic development, and that this has negative implications for health in developing countries. The latest AIDS vaccines have not been available in Africa, for example.

Contingent Contagionism

Lowing the development of smallpox inoculation (and later vaccination), inoculation directly into the body or the blood became recognized as a mode of transmission under the general category of contagion. A form of indirect contact was through fomites articles such as clothing and bedding used by the sick that harbored the shed virus and preserved its capacity to transmit disease for some period of time.52 Another route was infection, in which healthy people inhaled the virus after it was given off in the exhaled breath or from the skin pores of the sick person.53 Some medical men distinguished infection from true contagion, which they limited to transmission by touch.54 James Copland, a physician colleague of Snow's, was representative of those who believed in the infectious nature of pestilential cholera rather than contact contagion It was not caused or propagated by immediate or mediate contact by a consistent, manifest, or palpable virus or matter but by an effluvium, or miasm,...

Prevention of HAV Superinfection in Chronic Hepatitis B and CHC

HAV super-infection of individuals with chronic hepatitis B virus and chronic hepatitis C virus infection may exacerbate the liver disease, and, in some instances, may lead to acute liver failure (19,20). This concept has not been accepted by all workers in the field (21), but the recommendation that HAV-susceptible patients with chronic liver disease should be targeted for vaccination with one of the inactivated, whole HAV vaccines seems reasonable, and has become standard practice in many hep-atology centers. HAV vaccination of patients who have received liver transplants is also reasonable. Information about the immunogenicity of HAV vaccines in patients with chronic liver disease remains limited, but, in general, the immune response to the vaccines appear to be adequate in those with mild to moderately severe disease. In one study, the immune response to inactivated HAV vaccine among Chinese HBV-carrier children appeared to be reduced, compared to that in noncarrier children, but...

Future Problems in HBV Immunoprophylaxis

May arise de novo in infected infants, or can be transmitted from the mother (26). Available information (27) suggests that spread of these escape mutants may be slow, but modeling studies (28) suggest that they may become the predominant form of HBV by late in the twenty-first century. If this is correct, it will be necessary to incorporate mutantstrain antigens into future versions of HBV vaccines.

Culture medium composition

Propagation of viruses needed for vaccine development, almost all of the established cell-culture methodologies, especially with respect to culture nutrients, are designed primarily for the selection of proliferating cells. This remains true for cell cultures used to study membrane traffic, gene expression, transport, membrane electrophysiological properties, and intra-cellular signal cascades. The efforts undertaken to create culture media for the generation of non-proliferating, but differentiated, cells have been limited to the development of serum-free media supplemented with certain hormones, growth factors or chemicals 152 in most of the trials, no changes with respect to the basal composition of the media have been made.

Immunoprophylaxis Of Hepatitis D

Although pre-exposure administration of HBV vaccines will protect against HBV-HDV co-infections, HDV super-infection of individuals with established HBV infection remains a problem. HBsAg-positive hemodialysis patients, injection drug users, recipients of multiple blood products, individuals with multiple sexual contacts, and others at increased risk for HDV acquisition, would be potential candidates for immunoprophylaxis. Neither a HDV vaccine nor a high-titer anti-HDV immunoglobulin preparation are commercially available. Preliminary studies (29) of the immune response to HDV antigens, and to synthetic HDV peptides, have been less than promising, and progress in this field has been slow. As a result, the development of a HDV vaccine is not likely for some time.

Immunoprophylaxis Of Hepatitis C

Neither passive immunization with conventional or HCV hyperimmune globulin preparations nor active immunization with an HCV vaccine are currently recommended or available. Immunity to HCV infection is thought to be weak, and neutralizing, protective antibodies can be detected in only a small proportion of infected individuals, and seem to be isolate-specific. One consequence of this limited response is that superinfection by another HCV genotype may be identified in some patients chronically infected with one HCV genotype (30). The high frequency of mutations, in that portion of the viral genome encoding the HCV envelope proteins, may be responsible for the escape of the virus from antibody-mediated clearance. Early studies (31) suggested that primary infection with HCV did not induce protective immunity in the chimpanzee model of infection. However, there is evidence (32) that the immune response of chimpanzees to HCV may not be analogous to that seen in infected patients.

Progestogenonly Contraception

Medroxyprogesterone acetate and its metabolites are excreted in breast milk, so women who breastfeed should wait until 6 weeks post partum before starting Depo-Provera, when the infant's enzyme system should be more mature. Norethisterone enantate 200 mg (Noristerat) is shorter acting than Depo-Provera, 8 weeks, and is used to provide contraception after administration of the rubella vaccine, and until a partner's vasectomy has taken effect. It can also be used in the longer-term but only on a 'named patient' basis.

Mechanisms of Protection

Theoretically, if circulating neutralizing antibodies, directed to the immunodominant epitopes of HCV, are present prior to infection (as a consequence of vaccination or passive administration of antibodies), they may serve to protect susceptible hepatocytes from HCV infection during the initial viremic phase, by interfering with viral attachment and or entry. Additionally, they may protect uninfected hepatocytes during the likely secondary viremia or contiguous exposure to virus that results from production and release of virus from infected, injured cells, early in infection. However, if HCV is capable of evading neutralizing antibodies, a HCV vaccine that simultaneously elicited cell-mediated immunity might prove more effective than one that only evokes antibodies, because cellmediated immune responses may detect and destroy the initially infected cells, resulting in self-limited infection. This remains speculative, since the role of cell-mediated immunity in preventing HCV...

Process Related Issues

For industrial applications sterilization-in-place and cleaning-in-place, the degree of process automation, appropriate process control and monitoring of critical culture parameters as well as compatibility to up- and downstream operations are important issues for the choice of a reactor system. Furthermore, downtime and reliability of the bioreactor and process are other critical factors. These parameters are mainly dependent on the complexity of the operations, the operator skills and training. In a commercial context, scalability of the culture system has to be emphasized in particular due to the frequently enormous production capacities required to secure supply to the patients. Yearly production capacities of ten to hundred of kilograms were estimated for therapeutic monoclonal antibodies depending on the dose (348,416). Other examples demanding large production capacities are recombinant therapeutic proteins such as tPA, EPO, blood factor VIII (36), and vaccines used in broad...

Approach To Jaundice History and Examination

Hep Igg And Igm

Hepatitis A vaccination is available and recommended for those at high risk, including travelers to endemic areas, persons with chronic liver disease, men who have sex with men or children who live in areas with high rates of the illness. Household or sexual contacts of persons infected with hepatitis A can be offered prophylaxis with injections of immunoglobulin. Serologic studies, using several markers, are necessary to determine the presence and type of hepatitis B infection that is present. Hepatitis B surface antigen (HBsAg) is present in both acute and chronic infections. Its presence is associated with contagiousness to others. Patients with the e antigen (HBeAg) are 100 limes more infectious than those lacking the HBeAg. Antibody to the surface antigen (anti-HBs) is seen in resolved infections and is the serologic marker produced after hepatitis B vaccination. An IgM antibody to the hepatitis B core antigen (anti-HBcAg IgM) is diagnostic of an acute infection. A measurable...

To Probe Immunologic Sugar Moieties of SARSCoV

Glycan Array

SARS-CoV is a newly identified human viral pathogen that caused an outbreak of severe acute respiratory syndrome (SARS). Although substantial efforts have been made to study the etiological agent of the disease, the carbohydrate structures of SARS-CoV remain largely uncharacterized. This information is, however, very important for devising a vaccination strategy against SARS-CoV, as well as understanding the pathogenesis of SARS. To investigate this, we constructed glycan arrays to display carbohydrate antigens of defined structures and then applied these tools to detect carbohydrate-specific antibody fingerprints that were elicited by a SARS vaccine. Our rationale was that if SARS-CoV expressed antigenic carbohydrate structures, then immunizing animals using the whole virus-based vaccines would have elicited specific antibodies for these structures. In addition, if SARS-CoV displayed a carbohydrate structure that mimics host cellular glycans, then vaccinated animals may develop...

Other Gastric Helicobacter Species

In addition to H. pylori, there are five named, two proposed, and three uncultured Helicobacter species that have been identified in the stomach of different animal species (for review see ref. 1). Helicobacter mustelae causes gastroduodenal disease in its natural host the ferret (3), and provided the first animal model system that allowed for the study of host-to-host transmission, chronic gastritis, immunity, eradication, and candidate bacterial virulence determinants (using isogenic mutants) of a gastric Helicobacter species. Helicobacter felis naturally infects dogs and cats (9). It is probably not the most common gastric Helicobacter species in these hosts, and it is not clear how important it is as a cause of canine and feline gastroduodenal disease, but it was fortuitously found to readily infect the stomach of laboratory mice (for review see ref. 10). The rodent model of H. felis has been extensively utilized to investigate chronic gastritis, gastric atrophy (parietal cell...

Polyanhydride Products Made In Biomedical Field

Acoustic Wave Monodisperse Droplet

Core-shell microparticles are significantly more difficult to manufacture than solid mi-crospheres. A variety of techniques for fabricating microcapsules of varying sizes have been reported 32, 50, 65, 85, 87, 94, 120, 133, 134, 150, 172 . For example, variations of the common double-emulsion approach have also been used to prepare microcapsules by allowing the discontinuous phase of the primary emulsion to coalesce and form the core of the particle 50, 150, 172 . Such particles have shown an interesting pulsatile release profile that may be advantageous for vaccine delivery 150 . Important limitations of these approaches, however, are that the core and shell material must be immiscible and the microcapsule architecture is difficult to control the core size and shell thickness depend strongly on the properties of the primary emulsion and the time over which the emulsion is allowed to coalesce.

Drug Delivery Applications Of Nanogels

Recently, there has been significant interest in developing nonviral vectors for synthetic vaccines designed to prime the adaptive immune system that are sought for a broad range of infectious diseases and for the treatment of cancer in both prophylactic and therapeutic settings 250-252 . However, many obstacles associated with the successful delivery of synthetic vaccines remain such as antigen loading capacity, maintaining the integrity of encapsulated proteins, and minimizing the nonspecific antigen-antibody reaction. Therefore, the delivery system that can effectively carry the protein antigens to antigen-presenting cells is most desirable. The feasibility of achieving these goals has been demonstrated using submicron-sized hydrophilic particles, which were loaded with high doses of protein 253 .

Genetic Susceptibility to Chlamydia trachomatis Determines the Outcome of the Disease Data from a Mouse Model

In conclusion the host immune response to infectious agents may be of primary importance. The description of the immunoproteome, most frequently exploited in vaccine discovery, also correlates the hosts antibody responses, either protective or pathogenic, with the outcome of the disease. This kind of research is aimed at the development of new diagnostic prognostic markers.

Edwin Liu Liping Yu Hiroaki Moriyama and George S Eisenbarth Summary

Animal models have contributed enormously to study in the field of type 1 diabetes. Perhaps the most intensively studied model is the nonobese diabetic (NOD) mouse, which develops an autoimmune-mediated spontaneous diabetes associated with the development of insulin autoantibodies and insulitis. Accurate measurement of antiislet autoantibodies by radioassay and detection of antigen-specific T cells using major histocompatibility complex tetramers are possible. Various strategies have been developed in preventing diabetes in animal models a peptide-induced model of type 1 diabetes has been described. Finally, the development of pep-tide vaccines is hampered by the risk of anaphylaxis in both mouse and humans. In this chapter, methods and strategies to measure antiinsulin autoantibodies, to detect antigen-specific T cells by tetramer analysis, and to prevent diabetes using peptide vaccines are discussed. Along with these topics, a protocol of peptide-induced diabetes and peptide...

Displacing contingency bringing treatments in and out of focus

If it was important to situate the research work of the charity in a broader frame of reference, beyond the media fascination with 'predictive' genetic techniques such as genetic testing and or drastic interventions such as prophylactic mastectomy, one particular 'treatment', a drug for those with breast cancer, received much more attention in the publicity material of the organisation. From 1999 to 2001 the drug 'Herceptin', one of the first drugs to be derived from molecular-based knowledge of breast cancer, was mentioned in six different articles in a range of newsletters.5 Three of these referred to the fact that the organisation had made recommendations to The National Institute for Clinical Excellence (NICE) to support the licensing of the drug. Talked about in the popular press in terms of a 'vaccine' for breast cancer, the charity acknowledged that the story was 'a little more complex' than this, pointing out in one article how it was only suitable for only around 30 per cent...

Diabetes Prevention in the NOD Mouse

Finally, antigen-specific therapy is under study in type 1 diabetes and other autoimmune diseases for which the autoantigens have been identified. Potential autoantigens include insulin B-chain and insulin B 9-23 peptide, GAD, and heat shock protein (p277 peptide of HSP60). Autoantigen peptide vaccination is perhaps the most specific type of immunotherapy in both humans and the mouse, but has properties of a double-edged sword although such therapy may prevent diabetes, there is also potential to accelerate or even induce disease. The precise rules in immunotherapy to modulate the immune system toward disease induction or remission are not well understood, and it is likely that dose, timing, and route of administration will be important factors in the design of peptide vaccines.

Identification of Tularemic Antigens Recognized by Sera Collected from Naturally Infected Individuals

It is generally accepted that host defense against facultative intracellular pathogens, including F. tularensis, is based on cell-mediated immunity 31 . Nevertheless, both natural infection and vaccination with F. tularensis LVS induce strong simultaneous production of all three immunoglobulin classes 32 . Furthermore, it was proved for F. tularensis and for other intracellular pathogens like Ehrlichia chaffeensis and Salmonella enterica, that transfer of immune serum could induce some degree of protection 33-35 . Additionally, some tularemic antigens activate both cellular as well as antibody immune response in naturally infected individuals 36 . Therefore, knowledge about the tularemic antigens that trigger humoral immune response would be useful not only for diagnostic purposes but also for identification of candidates for vaccine development.

Biotech Industries

While other countries in Latin America may host pharmaceutical production, Cuba is heavily involved in research and development. Cuba entered the biotech industry in 1981 with the development of interferon, a potential cure for cancer. Centers of biotech research and development in Cuba include the Center for Biological Research (CIB), and the Center of Genetic Engineering and Biotechnology (CIGB), both located near Havana. Although the CIGB manufactures over a hundred products, from vaccines to transgenic plant sand animals, its major exports are two vaccines, one for hepatitis and the other for meningitis. The vaccines are exported to about 30 countries, especially developing countries. However, the United States is attempting to penalize multinational pharmaceutical companies that license the vaccines. In addition to vaccines and other pharmaceuticals Cuba's Center of Genetic Engineering and Biotechnology also produces genetically modified sugarcane, coffee, potatoes, and tomatoes....

Bacille Calmette Guerin

Live attenuated vaccines have reduced the incidence, and even eliminated, many important bacterial and viral diseases. The original BCG was derived between 1908 and 1921 by 230 in vitro passages of anM. bovis strain. This attenuated BCG was found to be nonpathogenic in guinea pigs, yet sufficiently immunogenic to protect against a challenge with virulent M. tuberculosis (48,49). In the preantibiotic era, the promise of an effective vaccine against TB made BCG popular and, starting in 1923, stocks were distributed around the world. BCG vaccination of newborns remains common in many countries with an estimated 100 million doses of BCG administered each year. BCG is safe and probably protects children against TB meningitis. However, in randomized controlled trials the efficacy of BCG against adult pulmonary disease has ranged from 0 to 80 , and remains a matter of debate (50,51). Efficacy may be diminished by prior exposure to environmental mycobacteria, which can alter the immune...

Resuscitation Promoting Factors

Tiple rpf deletions have yet to be tested. Analysis indicates that all M. tuberculosis rpf genes are transcribed during logarithmic growth. Expression patterns vary at intermediate time points, but all transcripts are also detected in 4-mo-old cultures. During the acute phase of infection, rpf expression is also present in M. tuberculosis from mouse lungs (156). Additional work on the immunological impact of Rpfs is required, but they have attracted some attention as vaccine candidates (157). Mycobacterial research is experiencing a renaissance. The wealth of genome sequence data, new molecular tools, plus bioinformatic, proteomic, structural, and functional genomic approaches hold substantial promise for understanding the biology of these unusual microbes, elucidating the molecular mechanisms of pathogenesis, and developing new chemotherapeutic agents and effective vaccines. These approaches ultimately should lead to the effective control of mycobacterial disease and end the scourge...

Antigen Presentation and Dendritic Cells

TABLE 1 Breast Cancer Vaccination Strategies There have been multiple clinical trials of vaccine delivery with the use of dendritic cells. The cells are usually isolated from peripheral blood by means of leu-kapheresis. They are cultured in vitro with the cytokines GM-CSF and interleukin-4, loaded with antigen, and matured ex vivo to enhance antigen presentation and costimulation of T-cells before being injected into patients. Antigen may be delivered as peptide, protein, RNA (53), or tumor lysates (54) (Table 1). In addition, dendritic cells have been directly fused with autologous breast cancer tumor cells, which allows for the presentation of multiple tumor antigens (55). Although dendritic cell-based vaccines have had minimal side effects and have induced measurable T-cell immunity, few durable clinical responses have been reported (55-57). However, a dendritic cell-based vaccine was shown to confer a modest survival benefit in hormone-refractory prostate cancer (58). Because...

Use Of A Loss Function Is A Clinical Trial For Inference Or Decision

The explicit use of utility functions within the design and monitoring of clinical trials is controversial but has been explored in a number of contexts for example, Berry and Stangl (1996a) discuss the problems of whether to stop a phase II trial based on estimating the number of women in the trial and who will respond in the future whether to continue a vaccine trial by estimating the number of children who will contract the disease and the use of adaptive allocation in a phase III trial such that at each point the treatment which maximises the expected number of responders is chosen.

Treatment of Autoimmunity in CLL

Only four of a series of113 splenectomies for AIHA were for hemolysis secondary to CLL (116). The well-known hazards of splenectomy are certainly increased in frail, elderly, immunodeficient patients. Laparoscopic splenectomy extends the possibility of operation to a less healthy population. Patients with AIHA with IgG alone and no complement components on their red cells respond better (117). Before elective splenectomy, vaccination against pneumococcus is recommended, and some groups also recommend long-term prophylactic penicillin or the equivalent.

Progress in Large Scale Cell Culture Technology

While small-scale cell culture provided sufficient products for investigational and diagnostic purposes, the demand for vaccines and therapeutic products required large-scale production. Some of the cell culture technology-based products such as monoclonal antibodies need to be manufactured at 1000 kg year. This can only be done in large bioreactors (up to 20,000 L) by efficient processes that produce several kilograms a day (1,7). Early cell lines used for vaccines were attachment-dependent cells. These cells required medium supplemented with serum and surfaces on which to grow. The expansion and propagation of cells required trypsinization. Scale-up of these systems was achieved by adding more surfaces into the bioreactor system. Roller bottles, T-flasks, and disk propagators are still used to scale up these cultures. A modernized version of these systems is the cell cube, which bears a similarity to a multichamber T-flask. Compared to suspension systems, attachment-dependent cell...

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