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...

The Revised Authoritative Guide To Vaccine Legal Exemptions Overview


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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...

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.

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....

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.

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...

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).

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...

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...

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,...

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...

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...

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...

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...

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....

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...

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...

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...

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.

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...

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...

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...

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...

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...


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...

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 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...

Future Considerations

Since Blumberg's discovery of the Australia antigen, progress in understanding HBV and the natural hepatitis B has been substantial. Effective and safe vaccination is now available to prevent new infections, and, for those infected, increasingly effective antiviral thers are available. Both of these interventions have already affected the natural history of hepatitis B. Future success in the struggle against hepatitis B infection will depend on universal application of vaccination programs, and the development of more effective multidrug combination thers aimed at multiple targets within the virion. With such advances, global eradication of hepatitis B within several decades is a realistic goal.

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 Persistence Of Sequence

What happens with food is mirrored in drug manufacture and administration. Many drugs are synergistic in their action for example, aspirin and codeine may be more effective as painkillers if given together than either by itself or both given separately. Aspirin, codeine, and caffeine taken together are a powerful combination and are most effective when combined in a mixture. Taking an aspirin, then a codeine tablet, and then drinking a cup of coffee one after the other is not as effective as taking a mixture of the three at one time. However, the effects extend further than this one drug combination may not be as effective as another even with the same ingredients the difference may be a subtle one and may depend not on the chemical content so much as on the mode of preparation. It is currently again in the news that the MMR triple vaccine (against measles, mumps, and rubella) given to children in Britain as a combined injection is alleged to have caused some cases of autism, while if...

Insights Basic Biology

To and is internalized by these cells. The secretion of proinflammatory cytokines and recruitment of phagocytes is effected by epithelia. However, macrophages may be used to disseminate infection through the circulation. This may also be true for T cells thus the organism seems to exploit the defenses used against it. Understanding both the primary and secondary immunological responses to this organism is critical for the successful design of vaccines. Rottenberg et al. have approached the problem of vaccine design with the aid of the recent sequencing of the organism. Vaccine candidates can be identified and studied in appropriate mouse models. However, a significant immunological question that must be addressed is the propensity for C. pneumoniae to enter a nonproductive growth state. Any successful vaccine strategy must be able to prevent and eradicate such cases.

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...

Targeting Bcrabl Rather Than Its Kinase Activity

The fact that Bcr-Abl kinase activity is central to its transforming potency has served as the rationale for the development of imatinib for therapy of Bcr-Abl positive leukemias. There is some evidence that targeting the kinase activity may have limitations. Some biological effects of Bcr-Abl are not kinase dependent, including effects on migration and adhesion (19). While these effects obviously do not prevent imatinib from inducing responses, it remains possible that they contribute to the persistence of minimal residual disease. Thus, eliminating these cells would require agents that target the Bcr-Abl protein rather than its kinase activity. Compounds with this activity include geldanamycin derivatives, which inhibit heat-shock protein 90 (HSP90), a molecular chaperone required for Bcr-Abl stability (45), LAQ824, a histone deacetylase inhibitor (46), and arsenic trioxide (47). Another possibility is that, the survival of primitive CML stem cells is independent of Bcr-Abl, relying...

Answers To Case 2 Health Maintenance Age 66 Years

Next step Each of the following should be performed Stool for occult blood, colonoscopy or barium enema flexible sigmoidoscopy, pneumococcal vaccine, influenza vaccine, tetanus vaccine (if not within 10 yr), cholesterol screening, fasting blood sugar level, thyroid function tests, bone mineral density screening, and urinalysis.

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

Selfantigens For Immunotherapy Of

The results of a phase I vaccine trial using a PRl peptide in patients with HLA A0201 have been reported. This trial included a total of 15 patients 6 with CML (interferon resistant or relapsed after stem cell transplantation), 8 with AML (smoldering relapse or > second CR), and 1 with MDS with no detectable antibodies to proteinase 3 (antineutrophil cytoplas-mic autoantibody negative). Patients were treated with three dose levels of PR1 peptide in incomplete Freud's adjuvant (Montanide ISA-51) and 70 g of GM-CSF every 3 weeks for three injections. Eight of 15 patients (53 ) had some evidence of immune response to the peptide vaccine as assessed by tetramer staining and flow cytometric detection of intracellular IFN-7. In this group, five patients experienced a clinical response, including three patients with a molecular response and one with a cytogenetic response. In one patient, tetramer sort-purified PR1-CTL obtained after vaccination showed PR1 specificity

Antibody Based Therapeutics

Antibody therapeutics can potentially treat diseases that can be as diverse as autoimmune disorders to cancer and infectious diseases. Antibodies are currently rated as an important and growing class of biotherapeutics. Other than vaccines, monoclonal antibodies currently in development outnumber all other classes of therapeutics. Recombination technology plays a key role in the development and commercialization of therapeutic antibodies. In fact, eight of nine antibody products on the U.S. market are recombinant products (57, 58).

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...

Concluding Remarks

Owing to the abundant experimental and clinical evidence, there should no longer be any doubt for the existence of cancer immu-noediting from immune surveillance to escape. Cancer cells are gradually able to gain several mechanisms of immune evasion during tumor progression even though they are pursued by the initial and continuing phases of immune surveillance. Immuno-logical sculpting contributes to immune selection pressure, which produces tumor cell variants that are resistant to immune effector cells due to their low immunogenic-ity. In advanced cancers, the marked shifting to immunosuppressive conditions due to the constitution of the immunosuppres-sive network in tumors makes it more difficult to provoke an immune activation to eliminate cancer cells. Given that adoptive immunotherapy using the peptide vaccine and DC transfer is not sufficient to reduce tumor volume and tumor elimination by direct priming for T cells in such conditions, indirect cross-priming for T cells, which...

Overview Of The Immune Deficits In Bcll

B-CLL is notable in that a significant proportion of patients develop infectious complications, which are associated with impaired immune responses. Because of the frequent bacterial infections seen early on in the disease course of B-CLL and the viral fungal infections seen later on or with therapy in B-CLL, investigations into the underlying causes have been undertaken. Early studies identified defects in both the humoral and cellular immune responses. Hypogamma-globulinemia detected by serum protein electrophoresis has been noted to occur in up to 70 of these patients (3), and significant declines in certain antibody classes have been demonstrated to correlate with disease severity (4). It is likely that up to 50 of patients with B-CLL sustain infectious complications during the course of their disease. Patients with hypogamma-globulinemia have more frequent infections with encapsulated bacteria, including Streptococcus pneumoniae and Hemophilus influenza (5,6). Not only is the...

Recombinant Dna And Genetic Engineering

Deoxyribonucleic acid is the cell's database. Within the base sequence is all the information necessary to encode RNA and protein. A number of biological and chemical methods now give us the ability to isolate DNA molecules and to determine their base sequence. Once we have the DNA and know the sequence, many possibilities open up. We can identify mutations that cause disease, make a human vaccine in a bacterial cell, or alter a sequence and hence the protein it encodes. The knowledge of the entire base sequence of the human genome, and of the genomes of many other organisms, such as bacteria that cause disease, is set to revolutionize medicine and biology. In future years the power of genetic engineering is likely to impact ever more strongly on industry and on the way we live. This chapter describes some of the important methods involved in recombinant DNA technology at the heart of which is DNA cloning.

Acute Pain 21 Immunizations

Immunizations are the most frequently occurring painful procedure in pediatric settings. These procedures have an enormous positive impact on disease prevention. For example, prior to the development of vaccines, there were 170,000 cases of diphtheria, 16,000 cases of paralytic poliomyelitis, and 500,000 cases of measles reported annually. In 2001, there were 2 cases of diphtheria, no cases of polio, and 116 cases of measles (9). It is obvious that the impact of these agents on reducing the burden of disease is almost incalculable. There has been steady growth in the number of immunizations given to children and adults. At the present time, according to the most recent immunization schedule, more than 20 immunizations are given to children by the age of 2 years and more than 26 throughout childhood. The sheer volume of immunizations has necessitated that multiple injections must be given at a health supervision visit. For example, at the typical 2-month visit, up to five separate...

Genome Of P Falciparum

In an international effort to accelerate the discovery of drugs and protective vaccines, the entire 22.8 Mb genome of the most lethal Plasmodium species, P. falciparum, which consists of 14 chromosomes, a linear mitochondrial genome, and a circular plastidlike genome, was published in October 2002 (Gardner et al., 2002). The falciparum genome is twice the size of the yeast Schizosaccharomyces pombe's genome, and represents the richest A+T genome sequenced to date (80.6 overall, and 90 in the introns and intergenic regions). The malaria genome sequencing consortium estimates that there were more than 5409 predicted open reading frames (ORFs) encoded in the P. falciparum genome, 60 of which lack sequence similarity to genes from any other known organism (Gardner et al., 2002). However, peptides from over 2400 of these ORFs have been detected by mass spectrometry, validating the gene prediction algorithms (Florens et al., 2002 Lasonder et al., 2002). Thus, almost two thirds of the...

Short Oligonucleotide Vs Long Oligonucleotide Microarray

Cluster exhibit gene ontology annotation, indicating their role in the establishment of the parasite into the red blood cell (i.e., early transcribed membrane proteins, erythrocyte-binding antigens, or genes involved in lipid and fatty acid metabolism). Hypothetical proteins that belong to this cluster are expected to perform similar functions. Cluster 15 groups genes that were highly expressed at the late schizont stage as well as genes involved in the invasion of the erythrocyte. Given that most of the genes considered as candidates for blood-stage vaccines reside in cluster 15, it can be reasonably assumed that the 90 hypothetical genes in this cluster could possibly be used in the development of new vaccines. Using this cluster analysis, more than 1000 genes within the malaria genome were given a hypothetical function and several numbers of them were seen as potential new drug or vaccine candidates.

Biological relevance of expression profiling

Significant advance for a better understanding of many hypothetical proteins in Plasmodium, there is still a need to maximize the vast amount of gene expression data sets to fully exploit the potential of high-throughput genomic approach and to narrow the research for identifying new targets. To make the most of high-throughput techniques, Zhou et al. (2004) used the high-density oligonucleotide array gene expression data sets to describe and apply a novel data-mining algorithm the ontology-based pattern identification (OPI). The OPI systematically discovers the expression patterns that best represent functionally related genes based on the principle of guilt by association. The OPI uses the gene ontology (GO) consortium to partially organize clusters. The OPI combined the malaria life cycle expression data sets with the Plasmodium gene annotation to begin with some a priori knowledge of the functional classification of a subset of genes and uses this functional information to...

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,...

Production of Mammalian Proteins in Bacteria

The large-scale production of proteins using cDNA-based expression systems has wide applications for medicine and industry. It is increasingly being used to produce polypeptide-based drugs, vaccines, and antibodies. Such protein products are called recombinant because they are produced from a recombinant plasmid. For a mammalian protein to be synthesized in bacteria its cDNA must be cloned into an expression vector (as described on page 139). Insulin was the first human protein to be expressed from a plasmid introduced into bacterial cells and has now largely replaced insulin from pigs and cattle for the treatment of diabetes. Other products of recombinant DNA technology include growth hormone and factor VIII, a protein used in the treatment of the blood clotting disorder hemophilia. Factor VIII was previously isolated from donor human blood. However, because of the danger of infection from viruses such as HIV, it is much safer to treat hemophiliacs with recombinant factor VIII. It...

Cytokine Regulation of the Acute Phase Response

The realisation that the response to illness and injury is an endogenous, not exogenous, process was a milestone in the understanding of cachexia. Our understanding that cytokines regulate the acute-phase response and cachexia resulted from several observations. For example, studies of hypertriglyceridaemia in experimental infections suggested indirect, or endogenous, control the degree of hypertriglyceridaemia was not necessarily correlated with infectious or tumour burden, and metabolic effects of infection could be reproduced with dead organisms or even with supernatants of macrophage cultures stimulated in vitro. The responsible protein was sought, isolated, and named cachectin, and its sequence was found to be identical to that reported for tumour necrosis factor (TNF) 5 . These studies concluded that this molecule was the mediator of cachexia. At approximately the same time, other investigators demonstrated that proteolysis in animals occurred after infusion of a...

Epidemiology and Pathogenesis

Mao et al. (2006) studied the natural history of high-risk HPVs in the control group of their HPV-16 L1 VLP vaccine clinical trial. They demonstrated that histologic changes become apparent shortly after HPV16 infection. In 11 of the 12 cases, CIN was identified 6-12 months after detection of HPV 16 DNA. Thus, years of persistent infection were not required before significant histologic changes such as CIN2 3 were seen. The median time to clearance of persistent infections (20.7 months) was similar to other previously published reports (Ho et al. 1995).

Immune Responses to HPV

Several studies have demonstrated that virus-neutralizing antibodies mediate protection of animals from experimental papillomavirus infection. For example, passive transfer of sera from virus-like particle (VLP)-vaccinated rabbits to naive rabbits is sufficient for protection (Bre-itburd et al. 1995). Similarly, vaccination with L2 peptides protects rabbits from papillomas resulting from viral but not from viral DNA challenge, consistent with the protection mediated by neutralizing antibodies (Embers et al. 2002). The well-characterized foreign (viral) antigens and the well-defined virological, genetic, and pathological progression of HPV have provided a unique opportunity to develop vaccines to prevent HPV infection and the associated pathology.

Antitumor Effects Of Mcp1 In Vivo

Effect of MCP-1 on tumor vaccination in rats. Rats were immunized with irradiated 9L glioblastoma cells (O), irradiated G418-resistant 9L cells ( ), or irradiated MCP-1-expressing 9L cells ( ). Two weeks later, immunized and nonimmunized ( ) rats were inoculated subcutaneously with 5 x 107 wild-type 9L cells, and tumor volumes were monitored. Fig. 1. Effect of MCP-1 on tumor vaccination in rats. Rats were immunized with irradiated 9L glioblastoma cells (O), irradiated G418-resistant 9L cells ( ), or irradiated MCP-1-expressing 9L cells ( ). Two weeks later, immunized and nonimmunized ( ) rats were inoculated subcutaneously with 5 x 107 wild-type 9L cells, and tumor volumes were monitored.

Establishing Target Cell Contact

The options for drug administration in vivo are oral and parenteral. For obvious reasons, gravitation and centrifugation are not suitable for targeting in this case. Oral administration of gene vectors localizes delivery to the gastrointestinal tract and promises great potential for genetic vaccination. Bacterial vectors 151-155 , viral vectors 156, 157 , chitosan-DNA complexes 158-160 , and microencapsulated nucleic acids or viruses 161-167 are used for this purpose. For details, the reader is referred to the cited literature. A complete review volume has been dedicated recently to microencapsulated DNA formulations for vaccination purposes 168 .

Scientific Foundations

DNA vaccines are made of gold particles. The particles are coated with a small, circular piece of DNA. The particles are injected into a person's cells, usually within a muscle because muscle cells are more receptive. The vaccine then delivers the DNA into the cells. The vaccine's DNA contains genes that code for a certain protein, called an antigen. This protein causes an immune response, just like a regular vaccine. The vaccine teaches the person's immune system to fight off the target disease. In the future, there may be other ways to deliver a DNA vaccine. A nasal spray is one possible method. The spray would carry the vaccine into the person's lungs, where the genes would be taken into lung cells.

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...

In Host Defense Against Tumors

Although the use of such cytokines either systemically or by expression as transgenes in transplanted tumor cells has shown efficacy in animal models, phase I human trials have yet to yield appreciable success (78-82). This failure could derive either from an inability to recruit appropriate cells to such sites or because the magnitude of the antitumor response is insufficient. Induction of localized chemokine expression at distant tumor sites could provide an important and complementary activity that could enhance this strategy. An alternative (though not mutually exclusive) approach involves the use of such tumor vaccines to promote the initial development of a specific antitumor response that could be amplified in vitro (83-88). Populations of specific antitumor T-lymphocytes might then be utilized in adoptive-transfer protocols, and some efficacy of this approach in animal models and phase I human trials has been reported (88,89). This may be an optimal setting in which to attempt...

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.

AntiCD137Mediated Suppression of Humoral Immunity

Characterization of the kinetics of anti-CD137-mediated suppression of T-dependent humoral immunity showed that the induction of suppression is restricted to an early phase of B cell activation. For example, we found that when mice were injected with anti-CD137 during antigen priming or within several days thereafter they failed to generate antibody responses to the immunizing antigen. However, when anti-CD137 injection was delayed until 10 days after vaccination,

Inhibitors of Viral Entry

The most ideal approach to inhibit HIV binding to the T-cells is to develop a vaccine that can neutralize the virus in circulation. Several attempts to develop antibodies to HIV as blocker for the viral binding to prevent infection have been reported (29, 30). However, because of the nature of the disease, people infected with HIV develop only low titers of neutralizing antibodies and that presents a problem for vaccine development. Knowledge of the detailed steps of the virus binding to the T-cell, together with discovery of the molecular structure of gpl20, CD4, and the chemokine as coreceptors for gpl20 binding, have directed vaccine development into more selective viral adsorption inhibitors (31).

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.

Needed HIV Drugs for Kids

As of 2006, there was still no proven vaccine for HIV. (A vaccine is a substance which, given to a healthy person, prevents them from being infected by a certain virus or bacteria one-celled germs that can cause diseases .) However, as of August, 2006, nine separate studies in the United States were testing experimental HIV vaccines.

Antitumor Immunity and B Cells

The notion that B cells might interfere with the induction of T cell mediated anti-tumor immunity was first suggested in experiments in which B cell development was blocked in neonatal mice that were subsequently inoculated with tumor cells. Compared with untreated littermates, tumor progression in these mice was markedly suppressed. More recently, Qin et al. demonstrated that it was possible to successfully vaccinate and protect BALB c MT B cell deficient mice against a variety of tumors (Qin et al., 1998). These studies strongly suggest that interplay between B cells and T cells suppress the development of anti-tumor immunity in MT mice. For example, these transgenic B cell deficient mice have the capacity to develop anti-tumor immunity following vaccination with irradiated tumor cells whereas syngeneic wild type mice do not. Adoptive transfer of B cells into na ve MT mice renders them refractive to vaccination and the mice succumb to the tumor (Qin et al., 1998). However, the...

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.

Induction Of Autoimmunity By

Was not observed or reported 34, 45, 81 , However, this might be due to natural resistance of the mouse strains used in these experiments against autoimmune diseases. The assumed association of stress proteins with endogenous self-peptide antigens in addition to tumor-specific peptide antigens causes concern that the vaccination with tumor stress protein preparations might induce autoimmunity in susceptible individuals. To address this concern, it has to be clarified what categories of endogenous peptide antigens are possibly associated with stress proteins

Epidemiology and Prevalence

HBV is endemic throughout the world, with populations showing a varying degree of prevalence. Approximately two thousand million people have been infected with HBV, with more than 350 million having chronic infection. Worldwide, HBV kills about 1 million people each year. With the development of a safe and effective vaccine in 1982, the World Health Organization (WHO) recommended that HBV vaccine should be incorporated into national immunization programs by 1995 in those countries with a chronic infection rate of 8 or higher, and into all countries by 1997. Although 135 countries had achieved this goal by the end of 2001, the poorest countries often the ones with the highest prevalence have been unable to afford it. In particular these include China, the Indian subcontinent, and Sub-Saharan Africa.

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.

Transmission Through Contact With Lesions or Organisms 61 Varicella Chicken Pox 611 Epidemiology and Prevalence

There is a strong correlation between a history of chicken pox and serological immunity (97-99 ). Most adults born and living in industrialized countries with an uncertain or negative history of chicken pox are also seropositive (70-90 ). In March 1995, a live-attenuated vaccine was licensed for use in the United States and a policy for vaccinating children and susceptible health care personnel was introduced. In summer 2002, in the United Kingdom, GlaxoSmithKline launched a live-attenuated vaccine called Varilrix. In December 2003, the UK Department of Health, following advice from the Joint Committee on Vaccination and Immunisation recommended that the vaccine be given for nonimmune health care workers who are likely to have direct contact with individuals with chicken pox. Any health care worker with no previous history of chicken pox should be screened for immunity, and if no antibodies are found, then they should receive two doses of vaccine 4-8 weeks apart. The vaccine is not...

Noncontributory Effects of Simian Virus 40 SV40 immunization contamination

Large quantities of polio vaccine administered during the period 1955-1963 were contaminated with SV40. SV40 DNA sequences have been detected in large proportions of ependymomas and choroid plexus tumors in some laboratory studies 42 , suggesting a role for SV40 in their etiology. No such association has been found in other series, however, including one of 33 ependymomas and 14 choroid plexus tumors from northern India, where the population has frequent contact with SV40-infected rhesus macaques 43 . Cohort studies of populations exposed to contaminated vaccines have failed to detect an increased risk. In some of these studies, not all vaccine was contaminated or the extent of use was poorly documented, but these criticisms do not apply to the most recent, large national study from Denmark 44 .

Management in Custody

Necrotizing fasciitis and septic thrombophlebitis are rare but life-threatening complications of intravenous drug use. Any detainee suspected of either of these needs hospital treatment. Advice about harm reduction should also be given. This includes encouraging drug users to smoke rather than inject or at least to advise them to avoid injecting into muscle or skin. Although most IDUs are aware of the risk of sharing needles, they may not realize that sharing any drug paraphernalia could be hazardous. Advice should be given to use the minimum amount of citric acid to dissolve the heroin because the acid can damage the tissue under the skin, allowing bacteria to flourish. Drugs should be injected at different sites using fresh works for each injection. This is particularly important when speedballing because crack cocaine creates an anerobic environment. Medical help should be requested if any injection site become painful and swollen or shows signs of pus collecting under the skin....

Granulocyte Macrophage Colony Stimulating Factor

Subcutaneous low dose GM-CSF is capable of recruiting and enhancing the activity of local antigen presenting cells, and this myeloid growth factor has been employed as an immunological adjuvant for antitumor vaccination in CML (19). GM-CSF may also improve the activity of IFN-a as primary therapy for CML (49), and a recent randomized study has explored the combination of GM-CSF and IFN-a in addition to high doses of imatinib as front line treatment for CML patients (50). The GM-CSF plus IFN-a arm of this study appeared to have a trend for improved CCyR and MMR rates at 12 months over the IFN-a only arm, although longer follow-up is required. Overall these data suggest that GM-CSF may enhance the activity of IFN-a against CML cells by boosting nonspecific antitumor immune effects. GM-CSF should also be evaluated in the context of MRD persisting on imatinib treatment.

Antibiotic Prophylaxis

Anyone with severe infection or who is clinically unwell should be referred to the hospital. Tetanus vaccine should be given if the primary course or last booster was more than 10 years ago. Human tetanus immunoglobulin should be considered for tetanus-prone wounds (e.g., soil contamination, puncture wounds, or signs of devitalized tissue) or for wounds sustained more than 6 hours old. If the person has never been immunized or is unsure of his or her tetanus status, a full three-dose course, spaced at least 1 month apart, should be given.

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.

General Information and Epidemiology

There are five serogroups of Neisseria meningitidis A, B, C, W135, and Y. The prevalence of the different types varies from country to country. There is currently no available vaccine against type B, but three other vaccines (A+C, C, and ACWY) are available. Overall, 10 of the UK population carry N. meningitidis (25 in the 15-19 age group) (59). Routine vaccination against group C was introduced in the United Kingdom November 1999 for everybody up to the age of 18 years old and to all first-year university students. This has since been extended to include everyone under the age of 25 years old. As a result of the introduction of the vaccination program, there has been a 90 reduction of group C cases in those younger than under 18 years and an 82 reduction in those under 1 year old (60,61). to be vaccinated with the quadrivalent vaccine (ACWY Vax) before going on a pilgrimage (Hajj or Umra), but illegal immigrants who have not been vaccinated may enter the country (62).

Prevalence and Epidemiology

With the advent of rapid identification tests and treatment and the use of Bacillus Calmette-Guerin (BCG) vaccination for prevention, TB declined during the first half of the 20th century in the United Kingdom. However, since the early 1990s, numbers have slowly increased, with some 6800 cases reported in 2002 (69). In 1998, 56 of reported cases were from people born outside the United Kingdom and 3 were associated with HIV infection (70,71).

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.

The Case Of Acquired Resistance To Autoimmune Disease

Beyond that demonstration of dominant tolerance in physiology, the reason to review this particular experimental system in the context of cancer immunity, is the well-established set of observations demonstrating that tolerance can readily be re-inforced and boosted by immunization. This was first suspected from the natural course of EAE, that spontaneously remits if the animal survives acute phase 9 , Moreover, new repeated attempts to re-induce another course of disease symptoms by secondary immunization systematically fail 10 . In other words, a primary activation of aggressive effector cells seems to reinforce the mechanisms that maintain tissue integrity (via inhibition of aggressive responses ). Demonstration that disease resistance resulted from activation of regulatory mechanisms was provided in various ways, one of which provided the basis for Cohen's T cell vaccination and bears legitimate hopes on future human therapeutic interventions for autoimmune disease. Thus, priming...

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.

Synopsis Of The Novel

Camus's The Plague, divided into five parts, chronicles the yearlong story of Oran, a dismal commercial seaport battling the plague. One fine April day in the 1940s Dr. Bernard Rieux, a 35-year-old physician preoccupied with sending his ailing wife to an out-of-town sanitarium, steps on a dead rat. Police magistrate M. Othon notices others. Later, Parisian journalist Raymond Rambert interviews Rieux for a story about lack of sanitation among the Arab population, but because the publication will compromise the truth, Rieux steers him to the dead rat story instead. Rieux's friend, Jean Tarrou, tells him about seeing more convulsing, dying rats. All but the doctor's mother, who comes to keep house for the doctor and his son, are unsettled by the events she has lived through war, depression, and a husband's death. Dead rats begin appearing by the thousands, then just when a sudden drop in the numbers causes the town to feel hopeful, the concierge M. Michel has fever, thirst, delirium, and...

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

Rock1 Kiaa0053 Homer 3b

Other candidates targeted by T cells include MUC-1 and members of the MAGE family of genes. MUC-1 is an immunogenic epithelial mucin present in several solid tumors and has also been identified on malignant plasma cells.62 68 MUC-1-specific cytotoxic T-cell lymphocytes have been isolated in the bone marrow of patients with myeloma.6269 Vaccination trials in myeloma are underway, targeting the MUC-1 anti-gen.7071 Genes of the MAGE family are expressed in myeloma and anti-MAGE CTL clones are identified and were able to kill myeloma cell lines in vitro.63

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...

Clinical Trials With Modified Dendritic Cells

A potential immunotherapy would require ex vivo-expansion of autologous DC from cancer patients, their exposure to tumor antigens, and reinjection into the tumor patients to induce tumor-specific T cells 87 . The most widely used method for generating CTL is to load previously defined immunogenic peptides onto DC prepared from blood of patients who express the appropriate HLA-restricting allele 88 . In man, Hsu et al. 89 have utilized autologous DC directly isolated from the peripheral blood of patients with B-cell lymphoma. In this neoplasm all tumor cells express the identical idiotypic protein on their cell surface that was used as tumor antigen. Each patient received several infusions of autologous antigen-pulsed DC. All treatments were well tolerated, and no side effects were associated with this type of vaccination. All four patients developed a specific cellular response against the idiotypic tumor protein. The antitumor immunity induced was associated with significant tumor...

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...

Infectious Complications

Showed that those with poor response to the vaccine (i.e., less than twofold increase or final specific IgG < 40 U mL) who also received IVIG had six episodes of infection compared with 16 episodes in poor respon-ders in the placebo arm during 128 patient-month follow ups (P 0.033).41 The short follow-up did not allow for survival analysis.41 The implication is that those patients who are unable to mount an immune response may benefit from IVIG during stable phase MM. Until further studies exploring risk of infusion reactions, overall survival, quality of life (QOL), and cost effectiveness are available, the routine use IVIG in stable phase MM patients is not routinely recommended. Similarly, there are no prospective data to suggest benefit from IVIG in MM patients with acute bacterial infections. Patients with hematologic malignancies often inquire about yearly influenza vaccination, and physicians differ on their recommendations. Data is available to guide decision making....

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