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; Read more...

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Period Of Vaccines And Uncertainty 19541975

The enabling period up to 1954 (Table 1.3) with the establishment of single cell culture (largely thanks to trypsinization), and long-term culture due to the advent of antibiotics, followed by the work of Enders and Salk, gave way to a period when vaccines were the only new products. The impetus for the rush of new vaccines (Table 1.4) in the late 1960s and early 1970s came about due to the establishment of the WI-38, and later the MRC-5, human diploid cell (HDC) strains and to standardization being brought out of the chaos in tissue culture laboratories described above. Salk polio vaccine 'Viral vaccines, uncertainty and chaos' Salk Polio Vaccine FMDV vaccine (large scale - 2 X 108 doses p.a.) Measles vaccine (WI-38) Rabies vaccine (WI-38) Mumps and rubella vaccines (WI-38) Varicella, CMV, TBE vaccines To summarize the position in 1975, viral vaccines were the only products. In human vaccine production the technology was simple, multiple flasks or roller bottles, dictated by the fact...

History Of Viral Vaccines

The first vaccine (Table 1.1), Jenner's smallpox (1798), was produced on the skin of living animals and was a very 'dirty' preparation. The next vaccine, rabies (1885) produced in spinal cord preparations, was equally contaminated with host proteins and caused severe anaphylactic shock and other side effects. The need for cleaner and safer vaccines led to the use of embryonated chicken eggs (yellow fever, 1935 influenza, 1936) and although an improvement, these preparations were still often contaminated with microorganisms. Thus the use of cultured primary cells was seen as a great breakthrough in terms of microbiological quality and purity (i.e. low levels of extraneous contaminating protein). However, subsequent research showed that monkey kidney cells were host to a wide range of intrinsic viruses such as a collection of simian viruses (SV), herpes B virus, etc. Some of these, like SV40, were known to be transforming viruses and thus concerns were felt over the possibility of...

Brief updates on priority current underused and new vaccines

While several existing vaccines, such as those against Hib, yellow fever, influenza, pneumococcus, Japanese encephalitis and rubella, are readily Table 3. Current and future vaccines and supportive technologies. Current vaccines New or improved vaccines Available but underused immunization supportive technologies Pre-f lied injection devices Vaccine vial monitors on all vaccines Meningococcus A (muiti-serotype conjugate)1 New combinations of existing vaccines' Pneumococcus (improved conjugate or prate in-based) Polio inactivated vaccines based on Sabin strains)c Jet injectors Thermostable vaccines Vaccine aerosols Vaccine nasal sprays Vaccine patches available but under-used, new vaccines against rotavirus, certain pneumo-coccal serotypes targeted with conjugate vaccines, meningococcus and HPV have recently been licensed and are gradually being introduced in high-income countries. At the same time, research on vaccines against major infectious diseases such as malaria, HIV AIDS, TB...

Characteristics of rotavirus important for vaccine development

The two outer capsid structural proteins of the rotavirus virion, VP7 and VP4, elicit the production of distinct neutralizing antibodies in the host and thus are considered important in vaccine development. The VP7 and VP4 also determine the serotype of the virus strain by the specificity of this antigen to elicit neutralizing antibody response in the host. The genes encoding these two proteins segregate separately, and this has led to a binomial system of classification for the VP7 glycoprotein (G types) and the protease-sensitive VP4 (P types) 32 . However, the importance of the neutralizing antibody response in vaccine development is less clear and will be discussed below. It is assumed that the neutralizing antibody response in the serum reflects the vaccine take and the magnitude of the response and the specificity of the immune response to the virus. Although at least ten VP7 G types are recognized among the human rotaviruses, five are identified globally to be common (G1-G4,...

Prospects for vaccine development

The application of molecular biologic techniques over the past decade has seen a tremendous growth in our knowledge of the biology of E. histolytica, and has led to the identification and structural characterization of three potential amoebic vaccine antigens the serine-rich E. histolytica protein (SREHP), the 170-kDa subunit of the Gal GalNAc binding lectin, and the 29-kDa cysteine-rich protein. Such a putative vaccine may be an oral combination 'enteric pathogen' vaccine, capable of inducing protective mucosal immune responses to several clinically important enteric pathogens, including E. histolytica (Ryan et al. 1997 Stanley 1997). An understanding of the amoeba's obligatory encystment pathway should provide an approach for interrupting the transmission (Eichinger 1997).

Project Title Development Of P53Based Vaccines For Oral Cancer

Summary (provided by applicant) Nearly 50 percent of oral carcinomas contain p53 mutations, making mutant p53 peptides attractive candidates for use in cancer vaccines. The probability is greater, however, that tumors will present wild-type sequence (wt) peptides derived from mutant p53 rather than mutant peptides. Our research is guided by the hypothesis that the effectiveness of vaccines targeting wt p53 epitopes will be influenced by (1) the ability of a patient's tumor to present wt p53 epitopes for immune recognition and (2) the ability of the patient's T-cells to respond to these epitopes. Our ongoing analysis of these factors, which focuses on the first of four CTL-defined wt p53 epitopes identified, p53, indicates that 1) nature or site of an alteration in p53 influences processing and presentation of this epitope and, perhaps, other epitopes as well 2) only a third of PBMC of either normal donors or patients responded ex vivo to this epitope and 3) tumors of responsive...

Posttransplant vaccination programme

The subject of re-vaccination post-transplant remains a contentious topic. The general principles are that live vaccination is forbidden, probably for the lifetime of the patient. Secondly, antibody and T-cell responses to vaccination in the first year following transplantation are sub-optimal. In allogeneic transplants, immune reconstitution continues beyond 1 and up to 2 years post-transplant. These general considerations have been used to suggest the following policy. Primary course of inactivated polio vaccine (3 doses). 336 Pneumovax II (repeated every 6 years). Influenza vaccine (and annually thereafter). The vaccinations should be staggered with only diphtheria and tetanus being administered concurrently. It would be reasonable to leave a gap of 2 weeks between each vaccination. Not only may this enhance antibody responses but it will easily identify the cause if there are any reactions. Inactivated polio vaccine booster. Influenza vaccine (repeated annually). Typhoid, cholera,...

Project Title Dnabased Vaccine For Treatment Of Oral Carcinoma

Summary Vaccine development for oral carcinoma is the current major research objective of my laboratory. The long-term objective is to develop a vaccine that can be used in the overall management of patients with squamous cell carcinoma of the head and neck (SCCHN). The vaccination strategy combines known requirements for generation of a robust anti tumor immune response--antigen presentation, allogeneic stimulation and the secretion of immune-augmenting cytokines. The vaccine is prepared by transfer of DNA from squamous carcinoma cells into a highly immunogenic syngeneic allogeneic cell line in which genes specifying tumor associated antigens (TAAs) are expressed. The recipient cells are modified in advance of DNA-transfer to secrete cytokines. This type of vaccine is based on the principle that TAAs are the products of mutant and dysregulated genes in cancer cells and that transfer of tumorDNA into recipient cells results in stable integration and long-term expression of the genes...

Vaccination Against Human Papillomavirus

Persistent infection with high-risk type HPV is a necessary cause of cervical cancer and therefore elimination of HPV infection will prevent this cancer (33,34). Furthermore, the majority of infections are cleared by the host's immune system suggesting the vaccination against this agent is feasible. Historically, vaccines have come to represent a highly cost-effective means to reduce the morbidity and mortality of infectious diseases. These facts have driven the rational development of preventative and therapeutic vaccination strategies based on the detailed understanding of the molecular biology of the HPV life cycle. Vaccination could be implemented to prevent infection (prophylactic) or eliminate infection (therapeutic), or optimally by combining both strategies in a preventive and therapeutic vaccine. The preventive vaccines typically elicit neutralizing antibody to interfere with HPV infection. The therapeutic vaccines would be likely to induce a virus-specific cellular immune...

Prophylactic Vaccines

The ultimate expression of medical success is prevention of a disease, and subsequently, its total eradication. It was not until the last case of endemic smallpox occurred in Somalia in 1977, with eradication of the disease declared shortly thereafter that vaccination was recognized as the means to eliminate diseases from the planet. The first mass vaccination strategy to prevent a cancer was the hepatitis B vaccine. Although, it has taken 20 years to demonstrate impact on hepatoma rates, the success of this preventive vaccine is now clear. Because the etiology of cervical cancer is infectious in nature, interfering with HPV infection with a prophylactic vaccine should theoretically prevent development of the disease and potentially achieve total eradication of cervical cancer and other HPV-related cancers. However, prophylaxis does not benefit those with preexisting disease. This is a significant issue because of the considerable burden of HPV infection worldwide. Furthermore, purely...

Vaccine Possibilities

Vaccination against Cn is another strategy to fight infection. One approach is the use of attenuated strains. Mice injected with an avirulent Cn strain that is unable to produce melanin are able to survive longer than control mice when subsequently challenged with more virulent strains (Barluzzi et al., 2000). More specific antigens may be useful vaccine candidates. Culture supernatants from Cn can elicit an immune response in mice. In combination with adjuvant, the supernatant can immunize T cell positive mice to better survive challenge with Cn infection. This is likely due to a combination of factors, since fractionation of the supernatant into mannoprotein and non-mannoprotein components results in partial protection by each component (Mansour et al., 2004). A third vaccination strategy is the use of peptide mimotope of GXM. The rationale for using such peptides is that protective antibodies against GXM have been isolated, but the peptide has fewer limitations than GXM for use as...

Evidence That Cell Vaccines Might Be Beneficial in Melanoma

Cell-based vaccines for melanoma have been evaluated in trials since the 1970s (Table 20.5). Melacine, consisting of two lyophilized melanoma cell line lysates administered with the Ribi adjuvant, and Canvaxin, consisting of three irradiated and frozen intact cell lines administered with bacille Calmette-Guerin (BCG), have been shown to mediate regression in a small proportion of patients with stage IV disease, in the range of 5 to 10 .102-105 Melacine was shown to have a 7 response rate in a small Phase II randomized trial with a survival no different from multiagent chemotherapy102 and has been tested in a large randomized Phase III trial as adjuvant therapy for patients with resected stage II melanoma compared with an observation arm.104,105 For all patients as randomized, there was no difference in overall and disease-free survival, but for patients who were HLA-A2 positive, a relapse-free survival advantage was seen, indicating that the HLA-A2 population might be appropriate for...

Development of Peptide Vaccines for Melanoma

Peptides of 8 to 10 amino acids are derived by intracellular cleavage of a variety of proteins, and are selectively conducted by the TAP transporter mechanism to the endoplasmic retic-ulum where they bind nascent class I molecules and are presented on the surface of the cell in association with class I molecules for interrogation by T cells. Because peptides are the smallest unit recognized by T cells, they might be useful as vaccine immunogens in the proper MHC class I context for recognition by T cells. A MAGE-3 HLA-Al-restricted peptide in aqueous solution was used to treat 39 patients with metastatic melanoma, of whom 26 finished four treatments every 4 weeks.112 Four PR as well as 3 CR were seen, often with a prolonged time to attain response 2 complete respon-ders had a duration beyond 2 years. The full-length MAGE-3 gene encoding the same peptide was chimerically linked to an H. Flu protein as adjuvant and used to vaccinate 35 patients in a Phase I trial with adjuvant...

Dendritic Cell Based Vaccines

Seven patients with metastatic melanoma received gp100 and MART-1 peptide-pulsed monocyte-derived DC.119 DC were administered intravenously four times at 3-week intervals in escalating doses. Only one of seven patients evaluated demonstrated an objective PR. Enhancement of CTL reactivity was seen in one of five patients who completed all four vaccines. Eleven stage IV melanoma patients received mature monocyte-derived DC loaded with a MAGE-3A1 peptide.120 The patients received five vaccinations at 2-week intervals. The first three vaccinations were administered subcuta-neously and the last two were administered intradermally. Six of 11 patients had regression of their disease. ELISPOT assays indicated that peptide-specific CTL precursors were expanded in 8 of 11 patients. Intriguingly, immune responses declined after the regimen of injections.

Developing vaccines against flavivirus diseases past success present hopes and future challenges

Vaccination still remains the most cost-effective way of protecting large populations against infectious disease. Safe and effective vaccines are available against most pathogenic flaviviruses and in recent years substantial progress has been made in developing vaccines against dengue. Dengue vaccines based on conventional and recombinant DNA technologies are being assessed and initial results are encouraging. Many other experimental vaccines have been developed, but despite the intensity of effort, concerns about the safety of new vaccines appear to be hindering their development. With the global threat from dengue increasing, might it now be the time to consider a less risk-averse approach

Commercially available vaccines

As they are agents of human and animal diseases with high morbidity and mortality, considerable efforts have been made to develop vaccines against several flavi-viruses (Stephenson 1988, Venugopal & Gould 1994). Theiler's seminal discovery in the 1930s that repeated passage in mice or tissue culture reduced the pathogenicity of yellow fever (YF) virus, produced the 17D vaccine virus which has proved to be both safe and efficacious over several decades (Freestone et al 1977). Similar successes have been achieved with conventional killed vaccines, especially against tick-borne encephalitis (TBE) (Heinz et al 1980, Popov et al 1985, Klockmann et al 1989) and Japanese encephalitis (JE) (Monath 2002), and a veterinary vaccine against louping ill (Brotherston & Boyce 1969) is also available. Three TBE vaccines are available from Baxter (previously Immuno), Chiron (previously Behring) and the Chumakov Institute for Poliomyelitis and Viral Encephalitides in Moscow. The former two...

Improving vaccination protocols

Conventional immunization strategies for inactivated virus vaccines usually involve the administration of at least two doses, several weeks apart. However, studies using a murine model of TBE have demonstrated that much more rapid vaccination protocols are possible (Stephenson et al 1995). In this experimental animal model, which mimics human disease in both pathology and route of administration, vaccination schedules lasting only 2-3 days were able to give complete protection against lethal encephalitis. Moreover, this protection could be elicited against virus challenge at soon as 5 days, or up to 100 days after vaccination was commenced. The mechanism of this rapid protection is unknown, although stimulation of innate immunity could play a role. Alternatively, as the virus infection takes 9-11 days to kill the animals the rapid vaccination protocols could give the host adaptive immune system a sufficient 'head start' in the race against virus replication. Immune stimulators have...

Dengue vaccines under development

Although conventional vaccines have played a major role in combating many fla-vivirus diseases such as YF, JE and TBE, developing vaccines against dengue remains a significant challenge. Following the success of using classical virological techniques to develop a live attenuated YF vaccine, similar methods have been used to produce a tetravalent dengue vaccine (reviewed in Halstead & Deen 2002). Two tetravalent vaccines using viruses attenuated by serial passage in non-human cells have been developed and are undergoing clinical trials. Both these vaccines have completed safety testing through phase 2 trials, and phase 3 trials are either underway or planned. One vaccine developed at Mahidol University in Bangkok and licensed by Aventis Pasteur produced 80 90 seroconversion rates in young children to all four serotypes after administration of two doses. However, the levels of immunity induced to some of the serotypes may not be sufficient to provide lasting protection against...

New approaches to vaccine design

Vaccines based of the envelope protein In addition to the whole genome vaccines described above there have been numerous attempts to use other strategies to produce vaccines containing the envelope proteins of several flaviviruses, especially dengue. Studies involving recombinant DNA viruses (reviewed in Stephenson 2001), and purified peptides (summarized in Volpina et al 2005) all report some measure of success in laboratory studies. Experimental genetic vaccines using plasmids containing the preM and E genes of many flaviviruses have demonstrated protection in animals (summarized in Timofeev et al 2004). Those against JE, WNV, Murray Valley encephalitis (MVE), dengue, TBE and louping ill all show protection in experimental murine models. Moreover, the JE vaccine has been shown to protect against disease in pigs, and that against WNV to protect against disease in horses. Studies on non-human primates are limited, but work on TBE and dengue has been reported. In all the work described...

Vaccine Safety Datalink A Special Purpose Database

In order to identify rare vaccine adverse events, the US Centers for Disease Control and Prevention (CDC) funded the Vaccine Safety Datalink (VSD), a large database that brings together computerized information on immunizations, medical outcomes, and potential confounders. Beginning in 1991, CDC joined with four HMOs, GHC, KPNW, Kaiser Permanente Northern California and Kaiser Permanente Southern California, all in the western part of the United States. Initially focusing on children up to 6 years of age, the database now includes adolescents and adults as well. All vaccinations given within the HMO study population, either routinely or for special indications, are computerized, including the vaccine type, date of vaccination, concurrent vaccinations, the manufacturer and lot number, and site of vaccination. Outcome data are collected from various sources at each site, such as hospitalizations, emergency department visits and outpatient clinic visits. To preserve patient...

Adverse Events Of Vaccine

Biologic products such as vaccines do not undergo the pharmacokinetic process that is associated with other drug therapies. Vaccines are generally safe. Some common mild reactions include swelling at the injection site and fever. Absolute contraindications for the use of vaccines include anaphylactic reaction to a specific vaccine or component of another vaccine or moderate or severe illness. Healthcare providers are expected to report vaccine adverse events to public health officials who report these to the CDC every week using the Vaccine Adverse Events Reporting System (VAERS), which is used to provide compensation for injury and death caused by vaccination.

Measlesmumpsrubella Vaccine

A study published in 1995 suggested that there may be a link between measles vaccination and the subsequent development of Crohn's disease and ulcerative colitis (Thompson et al., 1995). The study was reported by the Inflammatory Bowel Disease Study Group at the Royal Free Hospital School of Medicine in London. vaccinated group of 3545 people who had received measles vaccine in 1964 as part of a measles vaccine trial, (b) a control group of 11 407 people born in 1958 who were unlikely to have been vaccinated due to their age and of whom 89 had reported measles by age 11, and (c) a second control group of 2541 partners of individuals in the vaccinated group whose vaccination history was not known. Crohn's disease and ulcerative colitis were reported more often among the measles vaccine group than among the control groups. The difference in the prevalence of inflammatory bowel disease was significantly higher in the vaccinated group when compared with the unvaccinated group. It was...

Development of an AIDS vaccine

In excess of 40 million individuals are now thought to be infected by HIV. In 2001 alone, it was estimated that 3 million people died from AIDS and a further 5 million became infected with the virus. Over 20 million people in total are now thought to have died from AIDS. The worst affected geographical region is the southern half of Africa (Table 13.11). Some 90 per cent of sufferers live in poorer world regions. So far, no effective therapy has been discovered, and the main hope of eradicating this disease lies with the development of safe, effective vaccines. The first such putative vaccine entered clinical trials in 1987 but, thus far, no effective vaccine has been developed.

Immunity And Vaccination

Immunity is the ability to resist an infectious disease. A person who is resistant to a pathogen is said to be immune to it. One way for the body to gain immunity to a pathogen is to be infected by it, undergo a primary immune response, and survive the disease it causes. Another, safer way is through vaccination (vak-suh-NAY-shuhn), the introduction of antigens into the body to cause immunity. Vaccination usually involves an injection of a vaccine under the skin, as shown in Figure 47-8a.

Difficulties associated with vaccine development

A number of attributes of HIV and its mode of infection conspire to render development of an effective vaccine less than straightforward. These factors include After initial virulence subsides, large numbers of cells harbour unexpressed proviral DNA. The immune system has no way of identifying such cells. An effective vaccine must thus induce the immune system to (a) bring the viral infection under control before cellular infection occurs or (b) destroy cells once they begin to produce viral particles and destroy the viral particles released.

Vaccine For Primary Prevention Of Rf

Immunization is one of the most cost-effective means of preventing morbidity and mortality from infectious diseases. Routine immunization, particularly of children, has resulted in reported decreases of 90 or more in cases of measles, mumps, rubella, polio, tetanus, diphtheria, and pertussis. Vaccines also offer the opportunity not only to control but also to eradicate some diseases. The experience with smallpox has shown that the eradication of disease is a remarkably good economic and medical investment. Because of the biotechnology revolution, the development of a vaccine to prevent RF has made some headway. There are several different strategies currently being used to develop group A streptococcal vaccines, but the main focus has been based on the M protein.

AIDS vaccines in clinical trials

A number of approaches are being assessed with regard to developing an effective AIDS vaccine. No safe attenuated form of the virus has been recognized to date, nor is one likely to be developed in the foreseeable future. The high level of mutation associated with HIV would, in any case, heighten fears that spontaneous reversion of any such product to virulence would be possible. The potential of inactivated viral particles as effective vaccines has gained some attention, but again fears of accidental transmission of disease if inactivation methods are not consistently 100 per cent effective have dampened enthusiasm for such an approach. In addition, the stringent containment conditions required to produce large quantities of the virus render such production processes expensive. Not withstanding the possible value of such inactivated viral vaccines, the bulk of products assessed to date are subunit vaccines. Live vector vaccines expressing HIV genes have also been developed and are...

Conserved Domain Vaccines

Other investigators have used the highly conserved carboxy-terminal of the M protein to develop a broad-based vaccine. A collection of peptides from the carboxy-terminal region of the M protein is able to induce protection in mice, including prevention of pharyngeal colonization147'148 and protection from death after mucosal challenge.149 However, these epitopes occur in a region of the M protein known to induce host cross-reactive antibodies and T cells, making such a vaccine almost impossible to use in a clinical setting. Therefore, investigators have attempted to identify protective epitopes from the 'C' repeat region that are not host cross-reactive. One peptide known as p145 is recognized in more than 90 of individual sera. Minimal epitopes were then mapped from this peptide and using chimeric peptides, investigators were able to separate the minimal T- and B-cell epitopes within p145. This allowed the design of a vaccine that eliminates the potential of inducing harmful host...

Vaccines And Treatments

Scientists trying to create vaccines and treatments for HIV, such as the scientist shown in Figure 47-12, must contend with its rapid rate of evolution. The genes that code for the virus's surface proteins mutate frequently. As a result, new variants of the virus with slightly different surface proteins are constantly appearing. To produce effective immunity, a vaccine against HIV must stimulate the immune system to respond to many variants of the virus. Although researchers are developing and testing several vaccines against HIV, none has yet proven effective. In addition, HIV can quickly become resistant to drugs. Scientists now treat patients with a combination of three drugs. Because mutations are random, mutations that create resistance to all three drugs are not likely to occur. However, this therapy often requires patients to take 50 or more pills a day. Many HIV-infected patients find the plan difficult and expensive. Nevertheless, the multidrug treatment is the most effective...

Thiomersal To Be Removed From Vaccines

Because of the potential risks associated with thiomersal-containing vaccines, the US Public Health Service (PHS) and the AAP, along with vaccine manufacturers, the US Food and Drug Administration (FDA) and European regulatory agencies, have agreed that thiomersal should be removed from vaccines as soon as possible.760 2 The PHS and the AAP worked together to ensure that the replacement of vaccines containing thiomersal is managed as quickly as possible while maintaining high vaccination coverage levels in children. In September, the AAP published interim guidelines to clinicians on infant immunisation practices in light of concerns over thiomersal.777 2 The AAP believes that physicians should minimise children's exposure to thiomersal. However, they emphasised that the use of vaccines containing thiomersal is preferable to withholding vaccinations. In their opinion, the larger risks of not vaccinating children far outweigh any known risk of exposure to thiomersal-containing...

More Bad Press For Mmr Vaccine

The safety of the MMR vaccination was brought into question in 1998 following a report by UK researchers suggesting a link with inflammatory bowel disease (IBD) and autism.691 2 Concerns over the MMR vaccine were raised again in 1999 following the publication of another study by the same researchers in April linking atypical viral infections in childhood with IBD in later life.757 2 However, one of the study researchers, Dr Scott Montgomery, later emphasised that this study did not show any link between IBD and MMR vaccine, because they did not study the vaccine. The media coverage of the study findings was criticised by the UK Department of Health. Furthermore, a panel investigating the study concluded that there was no evidence indicating a link between the MMR vaccine and IBD (or autism) so there is no reason to change the MMR vaccination policy. Results of another study conducted by Professor Brent Taylor and colleagues from the United Kingdom also indicated that there is no...

Other Vaccine Adrs Refuted

In January, the safety of hepatitis B vaccine was questioned again by a US patient advocacy group who were concerned about the number of reports of serious adverse events and deaths in American children linked with hepatitis B vaccination.736 3 The hepatitis B school vaccination campaign was suspended in France in 1998 amidst concerns over a possible link with the onset or reactivation of multiple sclerosis and other demyelinating diseases. However, the available evidence does not demonstrate a causal association between hepatitis B vaccination and such diseases, according to the Viral Hepatitis Prevention Board, a WHO Collaborating Centre for the prevention and control of viral hepatitis.741 3 The Board concluded that there is no need to change current hepatitis B immunisation public health policies. Results of a large population-based study published in September also showed no evidence that recombinant hepatitis B vaccination is linked with demyelinating diseases.773 5 The possible...

Good News For Vaccines

After receiving a lot of bad press in 1998 and 1999, vaccines received mostly positive attention in 2000. The safety of hepatitis B virus (HBV) vaccine was questioned in 1999 because of a possible link with neonatal death in the United States. However, a review of reports received by the US national Vaccine Adverse Event Reporting System (VAERS) provided reassurance that HBV vaccine is not associated with an increased risk of unexplained neonatal death.786 2 The HBV school vaccination programme was suspended in France in 1998 amidst concerns over a possible link with the onset or reactivation of multiple sclerosis or other demyelinating diseases. However, results of a Canadian study published in February 2000 showed no evidence of an association between HBV vaccine and multiple sclerosis or post-infectious encephalomyelitis.789 4 Concerns over a potential link between measles, mumps and rubella (MMR) virus vaccine and inflammatory bowel disease and autism were first raised in 1998,...

Survey of Recombinant Viral Vaccines Currently under Development 6211 Herpes viruses

Genital herpes is caused by the herpes simplex virus type 1 or 2 (HSV-1, HSV-2), or human herpes virus 1 and 2 (HHV-1, HHV-2). Subunit HSV vaccines are based upon two envelope glycopro-teins, gB and gD which have been shown to be strongly immunogenic and protective in animal studies (Stanberry 1991). Four separate formulations have been evaluated to date, all derived from CHO expression systems. Three vaccines developed by Chiron contained truncated HSV-2 gD absorbed to alum, gD with a muramyl tripeptide adjuvant, and a bivalent vaccine composed of gD and gB with MF59 adjuvant. Although all these vaccines were immunogenic, the first was only modestly protective, the second caused unacceptable side-effects while the third failed to protect (Corey et al. 1999 Langenberg et al. 1995 Straus et al. 1994 Straus et al. 1997). The fourth vaccine (from GlaxoSmithKline) is also based on truncated HSV-2 gD and alum combined with the novel adjuvant 3-de-O-acylated monophosphoryl lipid A. This...

Expression Of Hiv Envelope Proteins An Hivaids Vaccine

It is no exaggeration to state that a greater effort has been committed to developing an effective vaccine against HIV than any other infectious agent. It is perhaps fortunate that the emergence of AIDS coincided with the blossoming of recombinant DNA technology and the promise of unlimited supplies of exquisitely characterised antigens, carefully honed to potentiate the components of the human immune system associated with HIV neutralisation or clearance. Unfortunately, despite 20 years of effort, no such vaccine yet exists. The most recent International AIDS Vaccine Initiative (IAVI) database (as of 13th June 2006) shows one Phase III, four Phase II and thirty-two Phase I trials in progress (http www.iavireport.org trialsdb ). Indeed, HIV vaccine development has driven the search for an ever-increasing range of vaccination technologies, ranging from initial immunisation with CHO-derived envelope subunits adjuvanted with alum, to complex prime boost regimes involving combinations of...

Impact of Genomics on Vaccine Design

Despite advances in the treatment of infectious diseases, pathogenic microorganisms are the single most important threat to health worldwide. Approaches to vaccine development have made remarkable progress in the last 200 years, and vaccination has prevented illness and death for millions of individuals every year. However, there are many infectious diseases still waiting for efficacious formulations, and many emerging pathogens. For these reasons, novel vaccines together with new ways to discover and produce them are needed. Most of the vaccines currently available are based on killed or live-attenuated microorganisms, toxins detoxified by chemical treatment or site-directed muta-genesis, purified antigens, or polysaccharides or oligosaccharides conjugated to proteins. Knowledge of the pathogenesis of many microorganisms, the identification of the main virulence factors, and characterization of the immune response after infection have been fundamental to the design of...

MenB Vaccine Approach by Reverse Vaccinology

The first example in which genomic technology has been used for the identification of potential vaccine candidates is the vaccine against the human pathogen Neisseria meningitidis serogroup B (MenB), the major cause of sepsis and meningitis in children and young adults. In the last forty years, conventional vaccinology approaches failed to provide an effective and universal vaccine against MenB. Although for other meningococcal serogroups (A, C, Y, and W135) conjugate vaccines based on the capsular polysaccharide are available and those based on oligosaccharides are under development, in the case of serogroup B the capsular vaccine cannot be used, as its capsule contains a major component (a(2-8)-linked To overcome this obstacle, the new approach named reverse vaccinology was applied to MenB 7 . The complete genome of the virulent strain MC58 was sequenced in collaboration with TIGR using the shotgun strategy. The MenB genome consists of 2 272 352 basepairs with an average G+C content...

The impact of genetic engineering on vaccine technology

The advent of recombinant DNA technology has rendered possible the large-scale production of polypeptides normally present on the surface of virtually any pathogen. These polypeptides, when purified from the producer organism (e.g. E. coli, Saccharomyces cerevisiae) can then be used as 'subunit' vaccines. This method of vaccine production exhibits several advantages over conventional vaccine production methodologies. These include Production of subunit vaccine in an unlimited supply. Previously, production of some vaccines was limited by supply of raw material (e.g. hepatitis B surface antigen see below). A number of such recombinant (subunit) vaccines have now been approved for general medical use (Table 13.9). The first such product was that of hepatitis B surface antigen (rHBsAg), which gained marketing approval from the FDA in 1986. Two billion people are infected with hepatitis B worldwide, 350 million individuals suffer from life-long chronic infection, and more Table 13.9...

Vaccines and Immunization Procedures

A vaccine is a preparation of a disease-causing agent or its products used to induce active immunity. Vaccines not only protect an individual against disease, they can also prevent diseases from spreading in a population. When a critical portion of a population is immune to a disease, either through natural immunity or vaccination, a phenomenon called herd immunity develops. 17.2 Vaccines and Immunization Procedures 421 This is the inability of an infectious disease to spread because of the lack of a critical concentration of susceptible hosts. Herd immunity is responsible for dramatic declines in childhood diseases, both in the United States and in developing countries. Unfortunately, we periodically see some of these diseases reappear and spread as a direct consequence of parents failing to have their children vaccinated. Table 17.1 lists a number of human diseases for which vaccines are available. As the table indicates, some are routinely used, whereas others are employed only in...

Traditional vaccine preparations

For the purposes of this discussion, the term 'traditional' refers to those vaccines whose development predated the advent of recombinant DNA technology. Approximately 30 such vaccines Table 13.5 Some diseases against which effective more effective vaccines are urgently required. Diseases more prevalent in developing world regions differ from those that are most common in developed countries Table 13.5 Some diseases against which effective more effective vaccines are urgently required. Diseases more prevalent in developing world regions differ from those that are most common in developed countries dead or inactivated bacteria (e.g. cholera and pertussis vaccines) live attenuated viruses (e.g. measles, mumps and yellow fever viral vaccines) inactivated viruses (hepatitis A and polio (Salk) viral vaccines) toxoids (e.g. diphtheria and tetanus vaccines) pathogen-derived antigens (e.g. hepatitis B, meningococcal, pneumococcal and Haemophilus influenzae vaccines). Table 13.6 Some...

Wildtype And Vaccine Strains Of Flaviviruses In Mosquitoes

It has long been known that whilst wild-type YFV can infect, disseminate and be transmitted by Ae. aegypti mosquitoes, the 17D strain, which is a live attenuated derivative used for human vaccination, can infect epithelial cells of the midgut but does not disseminate and is not transmitted (Roubaud et al., 1937 Whitman, 1937, 1939 Miller & Adkin, 1988 Jennings et al., 1994). Similarly, the YFV FNV vaccine strain is attenuated in mosquitoes (Davis et al., 1932 Roubaud & Stephanopoulo, 1933 Peltier et al., 1939). When Ae. aegypti is presented with virus in a blood meal (virus titres 7.2-8.3 log10 p.f.u. ml-1) dissemination rates ranged from 90 to 100 for wild-type YFV, but was only 3 for YFV 17D (Miller & Adkin, 1988). Jennings et al. (1994) also observed a lack of dissemination, but reported that midguts became infected with 17D. What seems to be operating to prevent dissemination of YFV 17D could be interpreted as an effective mosquito MEB. Although the MEB might be acting in...

Challenges to rotavirus vaccine development

What challenges can ostensibly remain for rotavirus vaccines, at the time that two safe and efficacious rotavirus vaccines are licensed internationally and on the verge of being introduced in multiple countries in the Americas and in Europe Certainly, these vaccines will reduce the tremendous costs associated with rotavirus-associated illness and hospitalizations. Nevertheless, for rotavirus vaccines to reach their full potential and impact significantly on reducing childhood mortality, the vaccines need to be introduced in the developing countries of Africa and Asia, where the bulk of global rotavirus mortality lies 5, 7, 8 . There are several challenges to the successful introduction and implementation of rotavirus vaccines in these regions 111 . The WHO has recommended consistently that the efficacy of the new generation rotavirus vaccines needs to be evaluated in the developing countries of Africa and Asia where the burden of disease and the mortality due to rotavirus disease is...

Barriers to vaccine delivery

Many concerns (e.g. reversion to virulence and recombination with other viruses) about the implementation of new vaccines, especially those against dengue, can be overcome by careful design, good quality pre-clinical research and careful monitoring during clinical trials. However, recent experience in many industrialized countries has shown that unpredictable societal issues can be a bigger barrier to successful vaccination strategies (Amanna & Slifka 2005). Political atrocities and influential local religious leaders have had a deleterious effect on polio vaccination campaigns in several countries. Fears of links between multiple sclerosis (MS) and hepatitis B vaccination, chiefly in France, have reduced uptake in those countries. The long running claims by a handful of workers that MMR vaccination is associated with Crohn's disease and autism has seen a dramatic reduction in vaccination rates in some parts of the UK and a consequential rise in measles cases. This has occurred in...

Response to Vaccination

Hepatitis B vaccination continues to be the best available means of preventing and controlling hepatitis B infection. Current recombinant hepatitis B vaccines achieve seroprotection in greater than 95 of the vaccinated adult population (172). However, approximately 5 of the adults respond inadequately to the standard three doses of hepatitis B vaccine. Those adults who have an antihepatitis B (anti-HBs) titer of less than 10 mIU mL are defined as poor- and nonresponders. The lack of anti-HBs antibody response has been attributed to many factors and these include improper storage, advanced age, gender, obesity, renal failure, and smoking (172,173). In addition, genetic factors, specifically the histocompat-ibility leucocyte antigens (HLA)-linked immune response genes may control the response to hepatitis B vaccine, and a poor antibody response is associated with certain HLA hap-lotypes. Earlier studies have found that immune response to hepatitis B vaccine is largely determined by the...

Vaccination In Transplant Recipients

Two issues limit the overall effectiveness of vaccination strategies in transplant recipients. First, transplant recipients may have declining antibody levels and diminished antibody responses to previous vaccine antigens once they become severely immunosuppressed (loss of previous immunity). Secondly, available evidence suggests that transplant recipients have diminished, although not absent, responsiveness to immunization (reduced vaccine efficacy). This is best demonstrated in kidney, liver and heart recipients after immunization with the pneumococcal vaccine. Solid organ transplant recipients require periodic assessment of immunization status for vaccine-preventable illnesses, beginning during the pre-transplantation evaluation. Routine immunizations are administered or updated as long as possible before the transplant to allow for the development of immunity these vaccinations include the hepatitis B series, hepatitis A, pneumococcal, yearly influenza, and tetanus-diphtheria. For...

Proteomics and Vaccine Design

Recent improvements in high-sensitivity biological mass spectrometry have provided a powerful adjunct to traditional 2D SDS-PAGE gel electrophoresis. The entire complement of proteins expressed by a cell (the proteome) can be defined and becomes a valuable and useful tool for antigen discovery 64 . This kind of approach has already been used to provide insight into the function of a specific subset of the proteome, such as the cell envelope of Salmonella typhimurium 65 . Proteome studies are made even more powerful when applied to an organism whose genome has been sequenced. In a recent study, Montigiani and colleagues used the approach of genomics combined with proteomics to characterize the surface proteins of C. pneumoniae 12 . Other examples where proteomics has also been used to study bacteria pathogenesis and identify vaccine candidates include Streptococcus agalactiae 66, 67 and H. influenzae 68, 69 . Further genome-wide studies are underway for S. aureus and Streptococcus...

Recombinant veterinary vaccines

Amongst the limited number of biopharmaceuticals approved for animal use, recombinant vaccines represent the single largest subgroup. Several such products target pigs, including 'Porcilis pesti' and 'Bayovac CSF E2'. Porcilis pesti, for example, contains a recombinant form of the classical swine fever virus E2 antigen, the immunodominant surface antigen associated with this viral pathogen. It is used to immunize young pigs. An overview of its manufacture is presented in Figure 13.14. The process is initiated by growth of Spodoptera frugiperda cells, typically in a 500 l fermenter. The cells are then infected with the recombinant baculovirus vector, resulting in high-level expression of the recombinant E2 antigen. The antigen is harvested from the production medium by low-speed centrifugation and membrane filtration steps, which serve to remove intact Figure 13.14 Overview of the manufacture of the veterinary vaccine 'Porcilis pesti'. Refer to text for specific details Figure 13.14...

Vaccine Delivery Systems

An important consideration in the development of vaccines is the mode of delivery. Development of vaccines against RF is focussed on the parenteral and the mucosal delivery of the vaccines. Administration of adjuvant potentially enhances the efficacy of a vaccine and alum is one of the choices, although the magnitude of the antibody response happens to be suboptimal. Human-compatible adjuvants that induce strong antibody responses are being investigated. It is generally believed that a mucosal vaccine is an optimal approach because the portal of entry of streptococcus is the nasopharynx. Fischetti38 investigated the role of IgA in immunity to group A streptococcal infection. Mice were protected against intranasal group A streptococcal challenge after passive transfer of affinity-purified human IgA to M protein M6. Mice immunized intranasally with conserved epitopes of M protein conjugated to the B unit of cholera could induce detectable levels of M-protein-specific salivary IgA and...

Peptide Vaccine Against Paracoccidioidomycosis

Other promiscuous peptides were recognized by 32-47 of patients 74 of patients recognized the combination of 5 promiscuous gp43 peptides (Iwai et al., 2003). An expansion of this study with 10 more patients (total of 29) showed that 79 of PCM patients recognized at least 1 peptide, and by pooling these peptides, the recognition frequency increased to 86 . The TEPITOPE algorithm scanned 25 Caucasian HLA-DRs and P10 and neighboring peptides were predicted to bind to 90 or more of these molecules. These results are the basis for devising a peptide vaccine against PCM that could be used at first as an immunological adjuvant to chemotherapy. The latter may involve a prolonged time and relapses are frequent. To test this hypothesis, immunization with peptide 10 and chemotherapy were used together in an attempt to improve treatment of experimental PCM and prevent relapses. Two protocols were used. Mice were infected intratracheally with yeast cells of P. brasiliensis and drug treatment was...

Rotavirus vaccine development

Rotavirus vaccine development was initiated relatively soon after the discovery of the virus due to the early recognition of the burden of disease and mortality in infants and young children universally. Within 10 years, rotavirus vaccine trials were being prepared utilizing a live attenuated oral vaccine approach based on several observations, including (i) that primary natural infection led to protection against severe disease upon re-infection 26, 70 , (ii) the antigenic relatedness of animal and human rotaviruses 34, 71 , and (iii) early animal studies that indicated that protection against rota-virus disease was mediated primarily by intestinal immunity 72 . Table 2. Live oral rotavirus vaccine candidates which are currently licensed or in clinical development Vaccine strain Type of vaccine Licensed vaccines NIH with vaccine producers in Brazil, China and India Although there are several licensed rotavirus vaccines and several under development (Tab. 2), the discussion in this...

Viral Vaccines

Studies with influenza A and paramyxovirus indicated that immunoprophylaxis requires the generation of an immune response to viral proteins that will protect individuals on exposure to the infecting virus. The proteins inducing such a response are termed 'protective antigens' and, in the main, are represented by surface-located glycoproteins in enveloped viruses and capsid proteins in non-enveloped viruses (Epstein et al. 1993 Tao et al. 2000). Some non-structural proteins have also been found to be protective, such as the NS1 protein of dengue, T antigen of SV40 and Tat and Nef of HIV-1. Currently (2006), 16 viruses are covered by licensed vaccines in the United States. These protect against adenovirus, hepatitis A and B, influenza A and B, Japanese encephalitis virus, measles, mumps, papillomavirus, poliovirus, rabies, rotavirus, rubella, smallpox, varicella and yellow fever. infection is by antibody, with the assistance of MHC Class II-restricted CD4+ helper T-cells (TH). Most of...

Fungal vaccines

Vaccination strategies against fungal infections involving live or attenuated fungi, cell wall, or cytoplasmic extracts and the transfer of passive or adoptive immunity had all been tried since the 1930s with little success. The coccidioidomycosis vaccine clinical trial conducted in the early 1980s by the Valley Fever Vaccine Study Group, did not succeed in producing distinct differences between immunized and placebo subjects (Pappagianis, 1993). The discovery of protective MAbs against C. albicans (Han & Cutler, 1995 Matthews et al., 1995) and C. neoformans (Dromer et al., 1987 Sanford et al., 1990 Mukherjee et al., 1992) has intensified the focus on antifungal humoral immunity. Although the list of potential fungal immunogens is expanding (Deepe, 1997), thus far, not a single fungal vaccine has been approved for clinical use. consistent with a Th1-type response (Svirshchevskaya et al., 2000). Active immunization with a tetanus toxoid conjugate of glucuronoxylomannan resulted in...

Tumour vaccines

Hepatitis B virus (HBV) vaccine is a widely used, very effective vaccine against hepatocellular carcinoma, while studies are in progress to develop vaccines against Epstein-Barr virus, which is closely linked to the development of Other obvious candidates for development of an anti-tumour vaccine are the human papilloma virus (HPV) and the human retrovirus, HTLV, which are causative agents for several human malignancies. While the development of a vaccine is obvious in a virally-induced tumour, in non-virally-induced tumours, the concept of a vaccine is more complicated. In this case, tumour cells or tumour cell extracts are used as cancer vaccines intending to enhance a humoral or cellmediated immune response to relevant tumour antigens, rather than to induce prophylactic immunity. The antibodies produced may kill the tumour cells by complement fixation or antibody-dependent cellular cytotoxicity, while the activation of cytotoxic T cells that recognize antigens on the tumour cell...

Therapeutic Vaccines

Infected basal epithelial cells and cervical cancer cells do not express detectable levels of capsid antigen. Thus, although L1 VLP and L2 vaccines may be protective, they are likely to be ineffective in the elimination of pre-existing infection and HPV-related disease. Currently there are more than 100 million infected women, 5 of whom are estimated to have persistent disease (80). Moreover, it is still possible that some viruses will breakthrough neutralizing antibodies induced by prophylactic vaccination and establish new infection. This is especially important because those VLP vaccines in the clinic are likely to protect against a limited number of HPV types. Given these potential shortcomings, additional measures to deal with established HPV infection and HPV-associated diseases are currently under investigation. Comparison of Prophylactic HPV Vaccine Antigens Comparison of Prophylactic HPV Vaccine Antigens

Vaccines

Preclinical and clinical trials are in progress to try to further enhance the specificity and efficacy of cyto-kines by using autologous tumor cells transfected with cytokines such as IL-2 (Bowman et al. 1998a,b), IL-12, GM-CSF, interferon gamma (Bausero et al. 1996 Yoshida et al. 1999),or lymphotactin as vaccines to stimulate the host immune response to the neu-roblastoma. Other vaccine approaches include the use of DNA vaccines (Pertl et al. 2003), or dendritic cell vaccines (Chen et al. 2003).

Vaccination

No vaccines, antibodies (monoclonal or polyclonal), or chemotherapeutic agents are currently licensed for use to prevent or treat hMPV infections. However, ribavirin and polyclonal antibody preparations (IVIG), used in the therapy and prevention of RSV infections in children, are known to have broad-spectrum activity and can inhibit different viruses. In tissue culture-based assays ribavarin and IVIG preparations containing high titers of hMPV-neutralizing antibodies were found to inhibit hMPV replication 77 . The clinical utility of these findings needs to be tested. The contribution of hMPV to pediatric RTIs suggests that it will be important to develop a vaccine against this virus in combination with those being developed for RSV and parainfluenza viruses. The circulation of two serotypes of hMPV might have implications for the development of vaccines. Studies in cynomolgous macaques showed that re-infection is suppressed by high titers of virus neutralization antibodies against...

Anti Idiotype Vaccine

Anti-idiotypic (Ab2) antibodies are potential tumor antigen surrogates (Kennedy et al. 1987). Ab2 can induce anti-anti-idiotypic antibodies (Ab3) that cross-react with the original target tumor antigen. As tumor vaccines, Ab2 antibodies have advantages over native antigens (e.g., carbohydrates) because they induce better T-cell help and stronger antibody response. Since they can be easily manufactured, and modified by genetic engineering, they are preferable to difficult chemical synthesis (e.g., complex carbohydrates). Anti-GD2 anti-idiotypic vaccines have been used successfully in tumor models (Cheung et al. 1993 Sen et al. 1998 Zeytin et al. 2000) and are being evaluated in patients with NB and melanoma (Foon et al. 2000 Batova et al. 2002).

Tumor Vaccines

Detailed analyses of more common tumors have identified immunodominant peptides recognized by either antibodies (SEREX) (Scanlan et al. 2002) or cytotoxic T lymphocytes (van der Bruggen et al. 2002). When combined with adjuvants, these purified proteins or peptides can be presented on APC in vitro or in vivo as vaccines to T cells. Alternatively, direct transfer of DNA coding for the immuno-dominant peptide or protein has also been successful (Pertl et al. 2003). While these approaches are underway for treatment of melanomas and carcinomas, they have not yet been pursued for NB. An alternative vaccine approach utilized whole tumor cells to provide a cocktail of antigenic targets. Pre-clinical analyses have utilized vaccines comprised of autologous or allogeneic tumor cells. Crude cell lysates have been superseded by in vitro expanded dendritic cells that have been pulsed with crude cell lysates. As APCs, Immunization with tumor cells genetically modified to express immuno-stimulatory...

Rotavirus Vaccine

In 1998, a tetravalent rhesus-based rotavirus vaccine was licensed in the United States for vaccination of infants. During the following 11 months, 15 cases of radiographically confirmed intussusception in vaccinated infants were reported to the United States Vaccine Adverse Events Reporting System (US Department of Health and Human Services, 1999a). Of the 15, most (87 ) developed intussusception following the first dose of the three-dose vaccination schedule. Eight of the children required surgical reduction and one, resection of part of the distal ileum and proximal colon. Following review of the data it was concluded that intussusception occurred with a significantly increased frequency after rotavirus vaccination (US Department of Health and Human Services, 1999b). Recommendations to vaccinate infants in the United States were subsequently withdrawn. The above reports of intussusception prompted an investigation to further evaluate the potential association with the vaccine...

Vaccine technology

The application of vaccine technology forms a core element of modern medicinal endeavour. It plays a central role in both human and veterinary medicine and represents the only commonly employed prophylactic (i.e. preventative) approach undertaken to control many infectious diseases. The current (annual) global vaccine market stands at in excess of US 3 billion. Immunization programmes, particularly those undertaken on a multinational scale, have served to reduce dramatically the incidence of many killer disabling diseases, such as smallpox, polio and tuberculosis. Continued increased emphasis upon the implementation of such immunization programmes is likely. This is true not only of poorer world regions, but also amongst the most affluent nations. An estimated 500 000 adults die annually in the USA from conditions that could have been prevented by vaccination. These include pneumococcal pneumonia, influenza and hepatitis B. Vaccination seeks to exploit the natural defence mechanisms...

Mprotein Vaccines

One strategy is to incorporate common, protective M-protein epitopes into vaccines that would prevent colonization of mucosal surfaces and thus interrupt infection at the earliest steps. A second approach is to incorporate type-specific, M-protein epitopes into multivalent vaccines that are designed to evoke serum bactericidal antibodies and mucosal IgA. Complete characterization of the M-protein molecule has allowed the development of M-protein-derived vaccines. Whole M-protein vaccines are not a feasible approach because of the cross-reactivity between the M protein and host proteins. Opsonic antibodies directed against the N-terminus of the M protein are mostly responsible for serotypic immunity. Therefore, the approach has focused on M serotypes, which would provide coverage against a large number of group A streptococcal strains. Two approaches that have been pursued by researchers of M-protein-based vaccines include identifying and combining multiple opsonic epitopes from the...

Cancer vaccines

The identification of tumour-associated antigens could pave the way for the development of a range of cancer vaccines. A number of tumour-associated antigens have already been characterized, as described previously. Theoretically, administration of tumour-associated antigens may effectively immunize an individual against any cancer type characterized by expression of the tumour-associated antigen in question. Co-administration of a strong adjuvant (see Section 13.5) would be advantageous, as it would stimulate an enhanced immune response. This is important, as many tumour-associated antigens appear to be weak immunogens. Administration of subunit-based tumour-associated antigen vaccines would primarily stimulate a humoral immune response. The latter approach has been adopted in experimental studies involving malignant melanoma. These transformed cells express significantly elevated levels of a surface glycoprotein, p97. p97 is also expressed (but at far lower levels) on the surface of...

Types of Vaccines

These are Attenuated whole agent. These vaccines are designed for people who have a normal immune system. The attenuated whole agent vaccine uses weakened living microbes to mimic the real infection to produce 95 percent immunity over a long term without the need of a supplemental vaccination called a booster. Common attenuated whole agent vaccines include those for tuberculosis bacillus, measles, rubella, Sabin polio, and mumps. There is a risk that live microorganisms or virus can regain their strength resulting in the patient contracting the disease. Inactivated whole agent. These vaccines are not designed for people who have an abnormal immune system. The inactivated whole agent vaccine uses dead microbes that were killed by phenol or formalin. Common inactivated whole agent vaccines include those for pneumonia, Salk polio, rabies, influenza, typhoid, and pertussis (commonly known as whooping cough). Toxoids. The toxoid vaccine is made of toxins...

Developing a Vaccine

Vaccines are developed by cultivating a large quantity of pathogen, which is a disease causing organism. Some pathogens, such as the rabies virus, can be cultivated in animals. For example, a chick embryo is commonly used to grow viruses and is the method used to develop the influenza vaccine. When vaccines were first introduced against measles and polio they would only grow in humans. However, with the development of cell culture techniques, cells from humans and primates enable large-scale viral growth. Scientists use recombinant vaccines because they do not need an animal host to grow the microorganism. An example is hepatitis B.

Genebased vaccines

Conventional vaccine technology, including the generation of modern recombinant subunit vaccines, has been discussed in Chapter 13. An additional gene-therapy-based approach to vaccination is also now under investigation. The approach entails the administration of a DNA vector housing the gene coding for a surface antigen protein from the target pathogen. In this way, the body itself would produce the pathogen-associated protein. Theoretically, virtually any body cell could be targeted, the only requirement being that target cells export the resultant antigenic protein such that it is encountered by the immune system. Additionally, gene expression need only be transient, i.e. just sufficiently long to facilitate the induction of an immune response. Target conditions for gene-based vaccines thus far having entered clinical trials include malaria, hepatitis B and AIDS.

Vaccine vectors

An alternative approach to the development of novel vaccine products entails the use of live vaccine vectors. The strategy followed involves incorporation of a gene cDNA coding for a pathogen-derived antigen into a non-pathogenic species. If the resultant recombinant vector expresses the gene product on its surface, then it may be used to immunize against the pathogen of interest (Figure 13.12). Most vaccine vectors developed to date are viral based, with poxviruses (as well as picorna viruses and adenoviruses) being used most. In general, such recombinant viral vectors elicit both Figure 13.11 Photographs illustrating some deanroom-based processing equipment utilized in the manufacture of SmithKline Beecham's hepatitis B surface antigen product. (a) A chromatographic fractionation system, consisting of (from left to right) fraction collector, control tower and chromatographic columns (stacked formation). (b) Some of the equipment used to formulate the vaccine finished product....

What Is a Vaccine

A vaccine is a suspension that contains a part of a pathogen that induces the immune system to produce antibodies that combat the antigen. The concept of a vaccine stems from the variolation process that was used in eighteenth-century England to protect people from smallpox. Edward Jenner noticed that dairymaids who contracted cowpox, which is related chemically to smallpox, were immune to smallpox. Jenner discovered that injecting cowpox into the skin of a healthy person prevented them from developing smallpox. Jenner's discovery enabled Louis Pasteur to develop the technique of creating vaccines. Vaccines play an important role in controlling the spread of viruses. A virus cannot be treated with antibiotics. However, you can minimize catching the flu by getting a flu shot, which is a vaccine against a particular strain of flu virus. Vaccines also prevent bacterial infections such as typhoid, but are not as effective on bacteria as they are on viruses. However, bacteria infections...

Peptide vaccines

An alternative approach to the production of subunit vaccines entails their direct chemical synthesis. Peptides identical in sequence to short stretches of pathogen-derived polypeptide antigens can be easily and economically synthesized. The feasibility of this approach was first verified in the 1960s, when a hexapeptide purified from the enzymatic digest of tobacco mosaic virus was found to confer limited immunological protection against subsequent administration of the intact virus. (The hexapeptide hapten was initially coupled to bovine serum albumin, used as a carrier to ensure an immunological response.) Similar synthetic vaccines have also been constructed that confer immunological protection against bacterial toxins, including diphtheria and cholera toxins. Although coupling to a carrier is Figure 13.10 Overview of the production of recombinant HBsAg vaccine (Recombivax HB Merck). A single dose of the product generally contains 10 ig of the antigen Figure 13.10 Overview of the...

Identification Of Cardiovirulence Determinants In The Cvb3 Genome

With the goal of ultimately describing safe efficacious vaccine candidate strains, mice have served as useful hosts in assessing cardiovirulence of CVB3 strains. Candidate mutant and chimeric variants of CVB3 (ie, molecular constructs composed of nucleotide sequences derived from cardiovirulent and noncardiovirulent CVB3 strains) have been tested. Cardiovirulence has been mapped to several different single nucleotides in the 5'-non-translated region,129'157 to an unknown sequence in the 5'-nontranslated region,52'158 or to VP2 in the capsid region.159 Additional genomic sequences that may contribute to cardiovirulence have been described as well as different multicompensatory nucleotide sequences that may be associated with cardiovirulence or attenuation.51 However, for most naturally occurring or laboratory CVB3 strains that have been molecularly analyzed, cardiovirulence maps to the 5'-nontranslated region.51

Biopharmaceuticals and pharmaceutical biotechnology

Although it might be assumed that 'biologic' refers to any pharmaceutical product produced by biotechnological endeavour, its definition is more limited. In pharmaceutical circles, 'biologic' generally refers to medicinal products derived from blood, as well as vaccines, toxins and allergen products. 'Biotechnology' has a much broader and long-established meaning. Essentially, it refers

Period Of Control Consolidation And Chemical Engineering 19751986

A problem besetting human vaccine manufacturers was the low productivity of cell cultures, in particular HDC, that were anchorage dependent (therefore needing a large surface area), and tended to grow only as a monolayer giving extremely low cell densities per unit area. Consequently, in this period huge efforts went into developing scaleable systems for mon-olayer cells with many ingenious chemical engineering methods being applied (Table 1.5). Although it was problem enough for vaccine manufacturers, who used systems employing up to 28 000 replicate roller bottle cultures a week, it was critical for a whole range of potential new products that were secreted from cells in low concentrations (Table 1.6). The diversity of cell culture systems developed (Griffiths 2000) is summarized in Table 1.7, and demonstrates alternative methods of overcoming the limiting factors in scale-up of increasing the surface area volume ratio, and overcoming nutrient and oxygen shortage and toxic...

Conclusions And Predictions

Decades have been spent searching for diagnostic tests whose results would covary with detection or severity of myocarditis induced in CVB3-murine models. Perhaps a potential method has been found in the use of polymerase chain reaction to monitor enteroviral RNA values in mouse hearts that develop chronic disease and are given various treatments. Quantitative values of viral RNA, cytokine mRNA profiles, or type of T-cell receptor in circulating leukocytes could have diagnostic significance for humans with heart disease due to CVB or even other viruses. With the abundance of myocardial tissues for sampling, the murine models offer the best approach for developing effective therapies, perhaps designing more heart-healthy diets or establishing new approaches to controlling unwanted immune responses in heart tissues. Murine models of CVB3-induced myocarditis have also confirmed and extended patients' data on virus-induced, potentially cardiopathologic, autoimmune responses, findings that...

The Genetics Of Cvb Cardiovirulence

The genetics of viral virulence phenotypes have not been worked out for any of the picorna-viruses, with the exception of the CVB, in which work has just begun. We distinguish here between the genetics of artificially altered virulence phenotypes (as, for example, by mutation or animal passage) and the genetics of naturally occurring virulence phenotypes, such as are found in clinical viral isolates. In the former case, the genetics and the mechanism of artificially induced attenuation have been worked out for the Sabin poliovirus vaccine strains,12,72-77 but the natural genetic determinants of the poliovirus neurovirulence pheno-type were never mapped. With poliovirus approaching worldwide eradication as a cause of disease,78-81 it is doubtful that this mapping will occur for poliovirus.

Principles Of Public Health

Though most governments recognize the importance of public health programmes in reducing disease and disability, public health generally receives much less government funding compared with other areas of medicine. In recent years, large public health initiatives and vaccination programmes have made great progress in eradicating or reducing the incidence of a number of communicable diseases such as smallpox and poliomyelitis. One of the most important public

Indications for Varicella Immunization

Age 12 to 18 months One dose of varicella vaccine is recommended for universal immunization for all healthy children who lack a reliable history of varicella. B. Age 19 months to the 13th birthday Vaccination of susceptible children is recommended and may be given any time during childhood but before the 13th birthday because of the potential increased severity of natural varicella after this age. Susceptible is defined by either lack of proof of either varicella vaccination or a reliable history of varicella. One dose is recommended. varicella by administration of two doses of vaccine 4 to 8 weeks apart.

Evidence For Hcv Involvement In Myocarditis

Model of flavivirus infection,175 thus raising the possibility of eventually deriving a murine model for flavivirus-induced myocarditis. Use of a transgenic mouse model176 to model anti-HCV protection using vaccinia virus-HCV chimeric vaccines has also been reported. GB virus-B is a member of the flavivirus family and is closely related to HCV. Bukh and colleagues177 have shown that GBV-B can replicate in tamarins and induce hepatitis, demonstrating a potential small primate model for HCV infection that might be adapted to heart disease.

Creating A New Vision

There are very interesting programs underway to examine the potential for various crops, including corn, rice, potato, taro, etc to be the mode of production and distribution of important vaccines and medicinal agents II . While there are important ecological concerns regarding these genetically modified crops, they may be the only economically effective way to bring preventative health care to hundreds of millions of people. In addition, local production of such health care agents will aid in developing the science and the technology of the country, as well improving the economic base.

Vectorborne Virus Diseases Yellow fever

In the 1930s, two live attenuated yellow fever vaccines were developed, a neurotropic vaccine obtained by multiple passages in mouse brain, and the better known 17D vaccine strain derived by passaging first in mouse brain and then in chicken tissue (Barrett, 1997). Both these vaccine strains have lost the ability to cause viscerotropic disease and do not replicate in the mosquito. The 17D strain, derived by Theiler in 1937 (Theiler & Smith, 1937), is now grown in embryonated chicken eggs, and some 20-25 million doses of vaccine for human use are produced annually in 11 different countries, much of it in Brazil and Senegal. This vaccine is one of the safest ever developed, and a single dose probably provides protective immunity for life (Monath, 2001), although revaccination after 10 years is required under International Health Regulations for a valid travel certificate. Unfortunately, the use of this vaccine in countries where yellow fever is endemic, especially in Africa, has been...

Current status remaining problems and progress achieved

The global immunization program has been supported by a degree of commitment and cooperation by the health sector and many other partners, within and outside of government, and from both the public and private sector, which has not been seen before for other health programs. However, the wider benefits of immunization are not reaching all children. Children in lesser developed countries still have less access to immunization services than those in wealthier countries, often because political commitment to, and funding available for, health is low, and health service delivery systems are weak and badly managed. Typically, the range of vaccines accessible to poorer children is smaller, and they are at greater risk from unsafe immunization practices. While some low-income countries have made substantial progress in increasing coverage, coverage remains low in others. In Europe, the economic and social changes following the break-up of the Soviet Union triggered a considerable decline in...

Current Applications And Challenges

The scope of natural immunity is vast and complicated by extraordinary diversity, redundancy, cooperation and amplification. Research to date has established the legitimacy of the field but the surge in exploration must continue if we harbour any desire to live in harmony with our immune system. Nevertheless, our increasing understanding of the mechanisms of the natural immune system and its importance for the development of a strong adaptive response has provided a strong incentive to better understand the dynamic interplay between infectious agents and host defence in man 34 and to develop new adjuvants as a component of improved vaccines. Current approaches to immune potentiation and adjuvant design combined with vaccine delivery are rapidly moving the field forward 81 . Toll-like receptors, in particular, are being targeted in vaccine development and in cancer therapy 82 .

Challenges For The Future

Health care purposes, there must be assurances that these materials are being developed in a sustainable manner. Natural products, both individual compounds and extracts, must be evaluated using the most current advances in drug discovery technology (automation, genomics, and bioassay targets). Rather than bringing dried (or fresh) plant materials to the laboratory for extraction and bioassay, there is a need to develop genomics-based, in-field bioassays which can evaluate plant extracts on site, so that recollection of an active plant can be made efficiently. There is a need to expand the number of natural products presented to systems for biological evaluation through chemistry, combinatorial synthesis, combinatorial biosynthesis, and other strategies. More feasibility and safety studies are needed to evaluate the potential for large scale drug and vaccine delivery through the use of genetically modified crops. The safety and efficacy, and the long-term consistency of...

Preface to the First Edition

Part I, Cellular Basis of Mucosal Immunity, provides an introductory overview and a historical perspective of the mucosal immune system (Chapter 1), followed by 10 comprehensive chapters (Section A) on development and physiology of mucosal defense (Chapters 2-11). These chapters address structure and function of mucosal epithelium, cellular basis of antigen transport, mucosal barrier, innate humoral factors, bacterial adherence, development and function of mucosal immunoglobulin, and epithelial and hepatobiliary transport. Section B (Chapters 12-19) focuses on cells, regulation, and specificity in inductive and effector sites. The inductive site chapters discuss characteristics of mucosa-associated lymphoid tissue (MALT), Peyer's patches, regulation of IgA B cell development, diversity and function of mucosal antigen-presenting cells, oral tolerance, peptidergic circuits, role of B-1 cells, and lymphocyte homing.The chapters on effector sites (Section C) present information about...

Biotechnology Development

There are numerous aspects of biotechnology which impinge on natural product drug discovery in addition to biosynthesis. These include the development of specifically modified bioassay systems and the translocation of whole biosynthetic gene systems for medicinally useful compounds from one, slow-growing, organism to another, faster-growing, organism of high biomass. For example, the ability to produce vaccines in staple food crops in order to provide or enhance immunity to disease in a population, will be crucial for the future improvement of global health care for certain disease states 11 .

Tickborne encephalitis virus

As methods of diagnosis of the disease have improved, involving testing of sera or cerebrospinal fluid for the presence of TBE-specific IgM and IgG antibodies using commercially available kits, the extent of the public health problem posed by TBE has been recognized, with 10000-12000 hospitalized cases annually. Control of tick populations was attempted in Russia but not found to be effective, and since the 1970s, inactivated vaccines have been developed and are available for human use in Europe and Asia (Barrett et al., 2003). In Austria, a high-risk country for TBE, vaccination rates now exceed 90 in some areas (Kunz, 2003).

Dual focus driving intentionality down and defining the biological contrasted with the physical

The same physical events, will lead that system to respond as if the state of affairs A exists. This echoes definitions proposed earlier of correctness and error in terms of functional activity. For example if the nerves leading from the baroreceptors are stimulated electrically over the range of frequencies that convey information about blood pressure changes the system will respond as if those changes had occurred. This principle is exploited in the production of some vaccines. The immune system normally responds to infectious agents, however molecules that resemble sufficiently the key features of those agents that trigger the immune response can also trigger that response.

The Application Of Molecular Forensics And Epidemiology To Viral Infections

Antigenic subtyping has been applied for many years to classify viral infections and outbreaks. Elaborate networks of surveillance teams, for example, are monitoring the antigenic characteristics and epidemiology of influenza virus strains isolated from infected patients, to determine the best vaccine cocktail to use in the coming year. The advent of rapid sequencing techniques has opened the door to obtaining detailed fingerprints of viruses that could provide important clues as to their source. In general, a selected region of the viral genome is sequenced from numerous isolates and subjected to

Burden of rotavirus disease

Rotavirus is the single most important enteric pathogen associated with high mortality in infants and young children in developing countries, and is associated with more than an estimated 600 000 deaths annually 4, 5 . Thus, new estimates indicate that rotavirus is responsible for 5 of total childhood mortality 5, 6 . The reported incidence rates of rotavirus infection do not vary significantly between industrialized countries and the developing countries of Africa and Asia, indicating that socio-economic improvements in water and sanitation may not reduce rotavirus diarrhea 7 . Nevertheless, the inequity in healthcare means that the vast majority of both diarrheal and rotavirus deaths are in children in the poorest countries of the world 1, 8 . In these poor countries, about 1 child in 200 will die of rotavirus disease 6 . This has prompted the international prioritization of rotavirus vaccines as a primary strategy for the reduction of the mortality associated with this infection....

Generation Of Viral Diversity

Homologous or nonhomologous recombination is another mechanism by which new viruses are generated and has played a significant role in virus evolution. Large DNA viruses can not only recombine with each other but also contain genes usurped from the host. RNA tumor viruses have incorporated cellular oncogenes that lead to transformation in some cell types. For RNA viruses, recombination probably occurs via incomplete synthesis and template RNA switching during negative-strand synthesis. This process occurs with high frequency in poliovirus infection, with an estimated 10 -20 of poliovirus genomic RNA recombining in a single growth cycle.5 In polio eradication efforts, a live virus preparation consisting of three separate attenuated poliovirus strains was used. Despite the safety of each attenuated strain, some vaccinated patients did develop poliomyelitis. Through genetic testing of patient isolates, it became clear that the recovered virus was not the same as the administered vaccine,...

Microbevector interactions in vectorborne diseases

Several billion people are at daily risk of life-threatening vector-borne diseases such as malaria, trypanosomiasis and dengue, and the dark shadow of plague hovers in the few endemic foci where it waits ready to re-emerge in a deadly pandemic. The abortive attempt to control malaria in the 1960s showed us the problem that we face in eradicating vector-borne diseases. Research into these tropical diseases fell into neglect during the 1960s, but in the 1970s research was once more directed towards vector-borne diseases and more recent initiatives such as the Roll Back Malaria Campaign have kept them in the international spotlight. If we are not to repeat the mistakes of the past it will be necessary to use all of our knowledge of vector biology. Written by international researchers in the field this volume describes the way in which pathogens interact with the vectors that transmit them. It details the elegant biological adaptations that have enabled pathogens to live with their...

Immunity against rotavirus infection

Rotavirus infection does result in both serum and intestinal antibody and in general does protect against severe diarrheal illness upon subsequent infection 22, 26, 30, 31 . Although the role of intestinal neutralizing antibody is generally accepted to play an important role in protection against disease, consistent results have been difficult to obtain, possibly due to difficulties in experimental design and the use of different animal models. However, questions do remain on what the actual mechanism(s) of protective immunity are and whether serum antibody, which is measured in all the vaccine trials, is indicative of clinical protection. Confounding results of the role of serum antibody have been identified in studies examining the natural history of rotavirus infection 31, 57, 58 , vaccine trials 56, 59 and adult challenge studies (summarized in 60 ). In brief, most studies have indicated that the presence of serum antibodies serves as a good surrogate...

In Vivo Generation of Antibody Against KLH Is a Measure of Acquired Immunity

And B cells, two primary players in acquired immune responses (8) the antibody response generated against KLH is similar to the immunological response generated after vaccination to tetanus toxoid (9) a reduction in specific antibodies to bacteria, virus, or soluble toxin could render the organism more susceptible to disease caused by these pathogens (10) KLH is clinically relevant because it is used as a immunotherapeutic in the treatment of cancer (Lamm, 1993 Jurincic-Winkler, 1995 Livingston, 1995 Gilewski, 1996 Jurincic-Winkler, 1996), and stress-induced modulation of the antibody response to KLH could affect the efficacy of this type of vaccination and immunotherapy (11) a final advantage to measuring aKLH responses is that the results we find in animals can easily be tested in humans (Smith et al., 2004a, 2004b).

Enzymelinked Immunosorbent Assay

The enzyme-linked immunosorbent assay (ELISA) provides a fast method to detect the presence of virus antigen or antibody from a large number of samples. Because of its reproducibility and flexibility, it is the most common serological assay used in the viral diagnostics lab. The general scheme is to capture virus antigens or virus-specific antibodies on a solid surface and to expose the bound complex with a substrate. ELISAs specific for IgM and IgG antibodies can distinguish between recent infection and previous exposure or vaccination. Detection of virus antigen indicates an acute stage of virus infection. The microtiter plate format can test multiple patient samples with different dilutions of antibodies to determine a serological titer, and sequential sampling of patient's serum over the course of an acute infection can allow detection of seroconversion. An increase in titers of IgG antibodies twofold to fourfold over 2 weeks is diagnostic of an active primary infection. ELISAs...

Dissociating enzymes and attachment factors

Like growth factors (noted above), the most widely used attachment factors in cell culture were historically derived from animal blood fractions (e.g. fibronectin, vitronectin). The response to animal origin concerns has been least successful for adherent cells. There exist multiple nutrient formulations that can support production applications of cells already attached in serum-supplemented media to harvest a target protein or vaccine for human or veterinary applications. Modifications to the basal medium may preferentially support cell attachment or synthesis of extracellular matrix elements. Substrata may be modified by charge density or impregnation of synthetic recognition sequences to enhance cell surface protein recognition and initial attachment. However, development of a stable, cost-effective serum-free medium for extended serial passaging of adherent cells without diminished performance has been elusive.

Mogensen et al 8Institute of Medicine

Complex Mixtures At the opposite end of the spectrum is exposure to complex mixtures, which can be intentional or unintentional. During the Gulf War, military personnel were intentionally exposed to vaccines and preventive agents including anthrax vaccine and the chemical warfare antidote pyridostigmines (9). Unintentional exposures included chemical biologic agents and smoke and petroleum combustion products. Potential exposures could have been through a combination of inhalation, oral, and dermal routes. Such mixed exposures were associated with symptoms such as fatigue, abdominal pain, diarrhea, headache, memory loss, skin rashes, and hair loss. Also, the exposure occurred under varying environmental conditions of temperature, humidity, and high winds. These types of complex mixture exposures pose a formidable challenge for health risk assessors. In general, the availability of information on chemical mixtures encountered in the real world varies greatly between simple and...

Variants And Related Syndromes

ADEM is most commonly seen in children and young adults, although it appears to spare very young children (< 2 years). It is related to recent infection or vaccination in the majority of cases, with the number of responsible agents being considerable, but measles, rubella, and varicella being among the most common precipitants. The clinical spectrum is very broad, from a subclinical course to fulminant, rapidly progressive disease with seizures and coma. Neurologic symptoms begin 1 to 3 weeks after the onset of infection, and symptoms peak within several days. Differentiation of ADEM from MS in adults can be very difficult, and we know that 35 of adult cases with a working diagnosis of ADEM have a second episode of neurologic disturbance compatible with MS within 12 months. MRI findings are often impressive, with extensive areas of demyelination considerable overlap with MS occurs. Basal ganglia lesions are seen in ADEM but not MS, but are only helpful discriminators in the small...

Engineering Novel Viruses Before and After Recombinant DNA

As mentioned earlier, viruses in nature, depending upon their replication strategy and host range, have many ways to evolve through mutation, recombination, reassortment, and selection. These innate properties have been used as tools in virology for decades. Examples include cold-adapted and attenuated live vaccine strains of influenza, cross-species rotavirus reassortants as vaccine candidates, and the attenuated yellow fever virus 17D vaccine strain that was counter to this idea. Viruses are usually highly adapted to a particular niche, and most mutations are deleterious. Propagation of pathogenic viruses in cell culture often leads to adaptation to that environment and attenuation in their animal host. Recombinants or chimeras between even closely related viruses are usually impaired relative to either parent. We do see examples, however, of viruses that are benign in one animal host but highly pathogenic in another species. This is often the case in epizootic emerging viruses. An...

What Are The Subdisciplines

Protein analysis, cell metabolism, biodiversity, biotechnology, downstream processing in chemical engineering, genetic engineering and vaccine designs and diagnostic kits are some of the important areas in which Bioinformatics constitutes an integral component. Bioinformatics relates itself with different entities. It may be classified on the basis of the level of investigations, species under study and different body conditions. Thus one can talk about DNA bioinformatics, mRNA bioinformatics, protein bioinformatics, cellular bioinformatics, microbial bioinformatics, parasite bioinformatics, human bioinformatics, physiological bioinformatics, pathological bioinformatics and developmental bioinformatics.

Kass E M Szianiawski W K Levy H Leach J Srinivasan K Rives C 1994

TBE vaccination and the Austrian experience. Vaccine 21, S1 50-S1 55. Suss, J. (2003). Epidemiology and ecology of TBE relevant to the production of effective vaccines. Vaccine 21, S1 19-S1 35. Willadsen, P. (2001). The molecular revolution in the development of vaccines against ectoparasites. Vet Parasitol 101, 353-368.

Preface to the Third Edition

Mucosal immunology has grown in the last decade from a discipline of perhaps peripheral interest to the mainstream immunologist into a major subspecialty with implications for the physiology of the entire immune system. An enormous and highly variable load of foreign substances, which includes indigenous mucosal microbiota as well as environmental and food antigens encountered mainly at the vast surface areas of mucosal membranes, has resulted during evolution in a strategic distribution of specialized cells involved in the uptake, processing, and presentation of antigens, the production of antibodies, and cell-mediated immunity at the front line of host defense. Furthermore, the great majority of infectious diseases and potential agents of bioter-rorism directly afflicts or is acquired through the mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts. In addition to the induction of protective responses to infectious agents, the unique immunoregulatory...

Sustained Eradication of Disease

Many reports confirmed the efficacy of DLI in inducing remissions in patients who have relapsed after transplant, particularly in patients with CML.186-188 DLI induces complete cytogenetic remissions in more than 70 in patients with CML when treated in either cytogenetic or hematologic relapse. Responses are noted in other diseases, including multiple myeloma, MDS, CLL, and low-grade lymphoma. Acute leukemia and advanced CML may be less sensitive to DLI. DLI can cause GVHD. However, it is exciting to note that DLI can induce remissions in the absence of GVHD, demonstrating that GVL and GVHD can be separable.189 The dramatic activity of DLI is what has led to the exploration of nonmyeloablative conditioning regimens in clinical situations that rely predominantly on GVL activity for therapeutic benefit. It is hoped that current efforts to identify targets of DLI will lead to generation of vaccines that can be tested in clinical trials.190,191

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