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 here...

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Clinical Trials of HIV1 Vaccine Candidates

In 2003, VaxGen announced that phase III efficacy trials of its gp120-based AIDSVAX candidate, aimed at inducing nAb responses, had failed to protect volunteers. The inadequacy of AIDSVAX and emergence of data suggesting CTLs play the major role in the control of HIV-1 heralded a paradigm shift away from the induction of nAb responses toward inducing CTL responses. Reflecting this, most of the vaccines currently on trial are based on strategies that have, as their primary or sole aim, the induction of CTL and T-helper responses against HIV-1. Thus, the main hypothesis currently being tested in clinical trials is that CTL responses can be induced safely in humans and will impact upon viral load and disease progression as they have done in primate models of simian-human immunodeficiency virus (SHIV) infection. In 2007, the phase IIb trials of the MRKAd5 trivalent vaccine developed by Merck & Co, which aimed to give 'proof of concept' for the CTL-based approach in man were...

Immunology and Vaccination

Particles of HPV-16 and HPV-18 consisting only of L1 protein have been developed as vaccines by Merck and GlaxoSmithKline, the product of the former company also including HPV-6 and HPV-11 capsids. The vaccines became available in 2006 07, and have been cleared by the Food and Drug Administration of the United States for prophylactic vaccination of women aged 9-26. Vaccination during extensive clinical studies efficiently protected PV-uninfected women against de novo PV infections over periods exceeding 5 years. The vaccinations led to the stimulation of humoral immune responses by more than an order of magnitude beyond levels found in natural infections. The success of this approach is apparently based on anti-PV immune globulin concentrations in cervical mucus

Recombinant Avipoxvirus Vaccines

Recombinant FWPV as a Vaccine Vector in Poultry Shortly after the development of methods for isolating recombinant VACV in the early 1980s, FWPV was developed as an equivalent recombinant vector for use in poultry. Several commercial vaccine and laboratory attenuated strains were used as vectors against a number of important poultry pathogens, especially avian influenza virus, Newcastle disease virus, infectious bronchitis virus, avian hem-orrhagic enteritis virus, Marek's disease virus, turkey rhinotracheitis virus, REV, and infectious bursal disease virus, as well as Mycoplasma gallisepticum. Commercial recombinant FWPV vaccines against Newcastle disease virus and avian influenza virus have been licensed for commercial use in the USA. Those against avian influenza have also been licensed for use in Mexico indeed, between 1997 and 2003, approximately 459 million doses of a recombinant fowlpox-H5 vaccine were used in Mexico as part of a program to control H5N2. The same recombinant...

Vaccines and Chemotherapy

Very successful live attenuated vaccines are in general use against certain 'respiratory' viruses like measles, mumps and rubella, which, though naturally trans mitted via the respiratory route, are absolutely dependent upon viremic spread to their target organs elsewhere in the body. In contrast, it is a much more challenging assignment to develop effective vaccines against viruses whose pathogenicity is essentially confined to the respiratory tract. The major reasons for this are that (1) secretory IgA memory is relatively short-lived, and (2) numerous antigenically distinct strains or serotypes are capable of causing the same clinical syndrome. Thus, a common cold vaccine might need to contain dozens of different serotypes of rhinoviruses ( coronaviruses). An inactivated vaccine is used to protect the aged and other risk groups against the currently prevalent strains of influenza, but its composition must be updated regularly to keep abreast of antigenic drift and shift and, even...

Factors Affecting the Feasibility of Vaccine Development

Table 3 lists some of the factors which make it more straightforward to develop a vaccine against a virus, and these can be contrasted with those which tend to increase the difficulty. It can be readily seen that most of the latter points apply to HIV. Ada GL and McElrath MJ (1996) Perspective. HIV-1 vaccine-induced cytotoxic T cell responses potential role in vaccine efficacy. AIDS Res. Hum. Retrov. 13 243. Ada G and Ramsay A (1997) Vaccines, Vaccination and the Immune Response. Philadelphia Lippincott Raven.

Conclusion Genomics And Vaccination

Despite the advances associated with molecular techniques, meningococcal disease remains a globally significant health problem, and the prospect of comprehensive vaccination remains elusive. Whereas vaccines based on the capsular polysaccharide are either licensed or under development against meningococci associated with serogroups A, C, and Y, as well as W-135, attempts to develop a polysaccharide-based serogroup B vaccine have proven unsuccessful. This fact is especially relevant as much of the meningococcal disease in Europe and North America is caused by meningococci associated with the serogroup B capsule. A number of alternative approaches to the development of serogroup B meningo-coccal vaccines are currently in development, 14 and these are summarized in Table 1. The recent completion of three meningococcal genomes (http www.sanger. ac.uk Projects N_menigitidis ) Refs. 23,24 has revolutionized the process of vaccine development and the application of genomic approaches such as...

Vaccine Clinical Trials

Similar to clinical development of drug products, there are four phases of clinical trials in vaccine development. Phase I trials are referred to early studies with human subjects. The purpose of phase I trials is to explore the safety and immunogenicity of multiple dose levels of the vaccine under investigation. Phase I trials are usually of a small scale. Phase II trials are to assess the safety, immunogenicity, early efficacy of selected doses of the vaccine, and generate hypotheses for later testing. Phase III trials, which are usually large in scale, are to confirm the efficacy of the vaccine in the target population and or proving consistency of manufacturing processes. Phase IV trials are usually conducted for collecting additional information regarding long-term safety, immunogenicity, or efficacy of the vaccine to fulfill with regulatory requirement and or marketing objectives after regulatory approval of the vaccine. In this section, we provide some design considerations,...

Two Main Requirements of a Vaccine

The safety of a candidate vaccine has become of prime importance. Most of the vaccines listed in Table 1 are very safe, but two in particular are less so. During the eradication campaign, most smallpox vaccines (vaccinia virus) had a level of side effects which made them unacceptable for current use. Safer preparations have since been made by the deletion of specific DNA sequences. Type 3 poliovirus in OPV can revert to virulence, and poliomyelitis occurs at the rate of about 3 X 106 doses of vaccine in recipients or their close contacts. Attenuated live vaccines may pose a risk to immunodeficient or -compromised people, but at least in the case of measles virus, even this is a very low risk. The second requirement is efficacy, which is assessed as the ability to protect recipients from disease after a subsequent exposure to the wild-type infectious agent. Vaccine efficacy depends almost entirely on the nature and persistence of the induced immune response. Vaccines are usually given...

Lessons from Successful Vaccines against Other Pathogens

Studies of the immune correlates of protection associated with existing vaccines reveal that Ab responses play a dominant role. Only BCG vaccination against Mycobacterium tuberculosis induces immunity in which Abs appear to have no role. Since CTL responses are likely to be required for an effective HIV-1 vaccine, traditional vaccine technologies are likely to be suboptimal, or counter-indicated due to safety concerns. Many existing vaccines are based on live-attenuated microorganisms. Such vaccines have potential hazards such as transmission to unvaccinated persons and the risk of reversion to pathogenicity, both of which have been observed with the Sabin oral polio vaccine. Killed microorganism vaccines do not have these drawbacks. However, they are occasionally associated with disease when the inactivation process is incomplete, and are inefficient at inducing CTL responses. Due to these factors, neither the live-attenuated nor killed vaccine approaches appear to be suitable for...

Immunization Vaccination

Although viral illnesses occur with high frequency and often devastating effect in transplant recipients, vaccination presently has only a limited role in disease prevention. There are a number of reasons why this should be so. Transplant patients are heavily immunosuppressed, and make poor antibody or T cell responses to killed subunit vaccines. Administration of live attenuated vaccines, which are potentially more immunogenic, is fraught with peril, since the immune response may be so feeble that even attenuated viruses may produce fatal disease. Finally, effective vaccines to herpes viruses in humans are simply not available. Since it is precisely that virus group which is responsible for most viral-related morbidity and mortality after transplantation, vaccination can at best have a limited impact on outcome. For example, several studies have examined the effect of attenuated Towne strain in renal transplant recipients. Unfortunately, the vaccine induces minimal specific cytotoxic...

Prevention and Vaccine

No vaccine is yet available and the only effective prevention at present is education about the ways of transmission, systematic testing of blood donors and the use of condoms. However, an important reduction of transmission from mother to child has been achieved by treatment with AZT of the mother at the end of pregnancy and at the time of delivery and of the newborn in the first weeks of life. A lighter regimen also seems to be effective and applicable to populations of developing countries. A complete control of the AIDS epidemic cannot be achieved without the availability of a protective vaccine. Although the use of whole virus or whole surface glycoproteins has been disappointing, there are new promising approaches based on the use of DNA, mucosal adjuvants and live vectors, internal and regulatory proteins, and conserved parts of the surface glycoproteins. The efficacy trials of candidate vaccine in large populations will raise important logistic and ethical issues difficult to...

Advantages of DNA Vaccines

DNA vaccines represent a new approach to immunization, in that an individual is directly inoculated (injected) with DNA that genetically encodes one or more of the antigens associated with the infectious agent. In effect, the recipient of a DNA vaccine produces the immunizing protein (antigen) within his own cells as a result of the immunization process. This revolutionary approach to vaccination offers many advantages over conventional vaccines. A major advantage is that DNA vaccination stimulates both the antibody and cell-mediated components of the immune system, whereas conventional protein vaccines usually stimulate only the antibody response. Furthermore, DNA vaccines are simpler to produce and store than conventional vaccines, and are therefore less expensive. Preliminary studies to date indicate that DNA vaccines appear to be very safe and to produce no side effects.

Vaccines And Diagnosis

Kinetoplastid CATB and CATL enzymes are potential candidates for vaccine development, either by preventing infection or decreasing pathology.4 Immunization of cattle with recombinant TcoCATL did not prevent infection with T. congolense but the vaccinated cattle maintained or gained weight and had less-pronounced anaemia during the chronic phase of the disease.76 Injection of mice with TcrCATL DNA stimulated cytotoxic T-lymphocytes that recognized and killed T. cruzi-infected cells.77 In other experiments, immunization of mice with recombinant TcrCATL conferred protection against experimental infection.78 Likewise, immunization with DNA plasmids encoding Leishmania CATLs resulted in protective immunity in murine models of cutaneous and visceral leishmaniasis.79-81 Finally, vaccination of BALB c mice with CATB was partially protective against Leishmania infantum infections.82

Fear of Autoimmunity Can Hold Up Vaccine Development

On a more negative note, a mistaken belief in autoimmunity can hold up vaccine development, as Kierszenbaum cogently argues for Chagas' disease 63 . This is a disease where a vaccine is much needed high disease prevalence in particular areas, lack of effective symptomatic treatment and lack of effective anti-parasite measures. Meningococcus B is another instance. Conjugate vaccine against Meningococcus C composed of capsular polysaccharide conjugated to a protein carrier is effective and now widely used. A similar vaccine against Men B has not been developed because of the danger presented by expression of a cross-reactive polysaccharide in neural tissue (Table 5). Instead, several serogroup B vaccines based on outer membrane vesicles have been shown to be immunogenic and reasonably effective in adults and older children, but the protection offered by them is chiefly strain-specific. Table 5 Where threat of autoimmunity impedes vaccine development Table 5 Where threat of autoimmunity...

Inducing Cell Mediated Immunity by Vaccination

In macaque models, vaccination with DNA plasmids or recombinant viruses bearing SIV SHIV antigenic inserts leads to significant attenuation of viremia after subsequent infection with the highly pathogenic X4-tropic hybrid isolate SHIV89.6P. Although they do not afford sterilizing immunity under any regimen tested thus far, such vaccines enable long-term suppression of viremia and prevent disease progression. Nonetheless, eventual escape of the challenge virus from CTL control after acquisition of single amino acid mutations in critical immunodominant epitopes is sometimes observed. This results in rapid rebound of viremia and normal disease progression, and underlies the necessity of targeting the most conserved epitopes critical for viral fitness, as well as targeting multiple epitopes if 'breakthrough' replication is to be avoided. A critical caveat of the work in macaques with the frequently used SHIV-89.6P is that this virus appears to be unusually sensitive to vaccine-induced...

Diagnosis Treatment And Vaccine

Two plague vaccines have been approved for use in humans. One is a formaldehyde-killed, whole-cell vaccine first used in 1942, and the other is a live vaccine used in the former Soviet Union since 1939. A new subunit vaccine that uses the bacterial capsular antigens F1 and V for immunization is under development.

DNA Vaccination Techniques

DNA vaccination involves immunization with a circular piece of DNA, known as a plasmid, that contains the gene (or genes) that code for an In many respects, this process is reminiscent of what occurs during a viral infection, when viral proteins are expressed within host cells. Thus, a DNA vaccine is somewhat like a very simple, nonreplicating virus. However, plasmid DNA vaccines do not replicate within the host, and therefore do not infect neighboring cells, as occurs during a viral infection. This innovation in vaccination strategy was discovered some years ago, but the active development of this technology only began after Stephen Johnston's group at the University of Texas Southwestern Medical Center demonstrated that plasmid DNA can induce the formation of antibodies against an encoded protein in 1992. Johnston's group was able to show that when mice are innoculated with plasmid DNA encoding human growth hormone, the mice produce antibodies against the hormone. There are two...

Vaccination

The first attenuated rinderpest vaccines were produced in the 1930s when the virus was adapted to replicate in goats (caprinized) and rabbits (lapinized). In the 1940s, a chick embryo-(avianized) adapted vaccine was produced. These vaccines were widely used but they had drawbacks in that they were not fully attenuated and could cause disease in more susceptible breeds. In the early1960s, a tissue culture-adapted strain of RPV, the 'Plowright vaccine', was developed by multiple passage ofthe virus in primary bovine kidney cells. The vaccine is relatively easy to produce, safe for use in all cattle breeds, and does not spread by contact. It is highly effective in preventing disease and the immunity induced in vaccinated cattle proved to be lifelong. This vaccine has been used successfully since the early 1960s for the control of rinderpest. A similar vaccine to control PPR was produced in the late 1980s by multiple passages of the virus on Vero cells and this is now being used to...

DNA Vaccination

Great excitement has greeted the possibility of using purified DNA encoding viral proteins to vaccinate against viral infections. The mechanism of presentation of DNA-encoded antigens to the immune system remains to be established but, in principle, DNA vaccination is similar to vaccination with infectious virus. Thus, the synthesis of viral proteins by antigen-presenting cells transfected by the vaccinating DNA will provide peptides to class I molecules, and viral proteins released from transfected cells should be processed and presented with class II molecules by professional antigen-presenting cells. Viral proteins released from transfected cells also stimulate B cells. Indeed, it has been found that neutralizing antibodies, TCD4+ and TCD8+ responses are induced following immunization in animals with DNA encoding influenza virus proteins. The immune response is, however, less potent than that obtained following immunization with live attenuated influenza virus, and it remains to be...

Vaccines

Two types of vaccines have been successfully tested in the SRV AIDS model. The first used a killed-virus formulation. The virus was inactivated with formalin and injected intramuscularly to induce antibody. The SRV challenge virus used to test the efficacy of the vaccine was prepared in isogenic rhesus monkey kidney cells, therefore ruling out induction of anticellular antibody as a protective mechanism. Protection was associated with neutralizing antibody. This was the first vaccine shown to be effective against a primate retrovirus. The second vaccine used a recombinant vaccinia virus vector. The vaccinia virus vector expressed the envelope proteins (gp70 and gp20) of SRV-1 and MPMV. Upon challenge with live SRV-1 by the intravenous route, both MPMV- and SRV-1-immunized animals were protected. The vaccine therefore conferred cross-protection for SRV types 1 and MPMV, demonstrating in vivo their close relationship. The neutralizing antibody did not cross-react with the more distant...

Classic Vaccines

One of the greatest achievements in the history of medicine has been the development of vaccination. The use of vaccines has saved more lives than all other medical procedures combined, and represents one of the highest points in civilization's technical accomplishments. Vaccines are used to mobilize the immune system to prevent or combat infectious disease caused by exposure to viruses, bacteria, or parasites. A vaccine works by mimicking an infectious agent and inducing a protective immune response in the host, without actually causing the disease. Successful vaccination provides protection for individuals by making them immune to the disease, and it protects whole populations by hindering the spread of the infectious agent. Historically, vaccines have consisted of formulations using live, noninfectious (attenuated) microbes that resemble the original pathogen whole organisms that have been killed or purified by-products of the infectious agent. More recently, some vaccines have...

Prevention and Therapy

In the USA, orally administrate, live, enteric-coated vaccines against HAdV-4, HAdV-7, and HAdV-21 were used in military units for a couple of decades. After the cessation of vaccine production in 1996, the impact of adenovirus infection among military recruits increased, and re-emergence of HAdV-7 and especially HAdV-4 has been verified. Since 1999, 12 of all recruits were affected by adenovirus disease. Efforts to resume vaccination are in progress. In the veterinary practice, dog vaccination schedules all over the world invariably include a live or killed CAdV-1 component against dog hepatitis. Inactivated vaccine for horses against equine adenoviruses has been prepared in Australia. In farm animals, inactivated bivalent vaccines (containing one mastadenovirus and one atadenovirus) have been in use in several countries for controlling enzootic calf pneumonia or pneumo-enteritis. In poultry practice, commercially available or experimental vaccines for the prevention of EDS or turkey...

Prevention and Control

Killed and attenuated live vaccines for EAV and PRRSV are commercially available. The live vaccines are more effective and induce a longer-lasting immunity than the killed vaccines. Although animals immunized with the live vaccines are protected from disease, they are not protected from reinfection and can spread virus. Current serological assays can not distinguish field strains from vaccine strains.

Future Perspectives

Arteriviruses have so far been isolated from mice (LDV), horses (EAV), pigs (PRRSV) and monkeys (SHFV). It seems likely that other host species, including humans, may harbor additional members of this virus family. Such viruses will be especially difficult to find in natural hosts that develop asymptomatic infections. Because of the inapparent and persistent nature of infections caused by LDV, PRRSV, SHFV and EAV it is important to develop rapid and reliable diagnostic tests for these viruses to easily identify infected animals. The availability of complete genomic sequences for EAV, PRRSV, SHFV and LDV should facilitate the development of new diagnostic assays and vaccines and may also provide the means for detecting additional arteriviruses. See also Immune response Cell mediated immune response, General features Vaccines and immune response.

Transmission and Tissue TTopism

Transmission of virus is principally vertical by infection of the offspring through virus secreted into the egg. Indeed, high titers of ALV are often detectable in commercial hen's eggs. Horizontal spread of virus is naturally much more rare, requiring close contact, but virus can be readily spread from infected birds via contaminated needles during vaccination or through vaccines prepared from infected eggs or cell cultures.

Release of First MLV Followed by Reports of pvMD

Because cytopathic strains could be more easily detected, quantitated, and studied in tissue culture than noncyto-pathic strains, the discovery of cytopathic BVDV was a boon to the study of BVDV. In 1964, the first cytopathic BVDV strain discovered (Oregon C24 V) was incorporated into a modified live multivalent vaccine. Soon it was reported that subsequent to use of this vaccine a minority of animals became sick with MD-like symptoms and died. These cases were referred to as postvaccinal MD (pvMD). Further investigation revealed that the vaccinated animals that succumbed to pvMD responded with serum antibodies to the other components of the vaccine but did not respond to the BVDV component. This suggested that the susceptibility to pvMD might be correlated with failure of the immune system to recognize BVDV. Questions raised by pvMD lead to the elucidation of the etiology of MD.

Segregation of BVDV into Two Genotypes

Studies done in the late 1980s and early 1990s, comparing vaccination cross-protection and monoclonal antibody binding, revealed antigenic variability among BVDV strains. While these studies indicated that there was considerable variation among BVDV strains, no standard means of grouping viruses based on these variations was generated. Meanwhile, based on hybridization analysis and sequence comparison, several groups evaluated the 5' untranslated region (UTR) as a target for polymerase chain reaction (PCR) tests designed to detect the wide range of BVDV strains or to differentiate BVDV strains from other pestiviruses. pathogenesis of BVD-MD. However, the recognition of hemorrhagic syndrome in the late 1980s and early 1990s brought the concept of severe acute BVD once more to the forefront. Case records of cattle admitted to the Cornell College of Veterinary Medicine for the years 1977-87 revealed that 10 of clinically acute BVD infections in adult cattle were associated with...

Molecular Testing In The Epidemiological Typing Of B Pertussis Isolates

The finding that the currently circulating strains harbor ptxS1 and prn alleles different from those in strains used for vaccine production emphasizes the importance of monitoring the molecular evolution and antigenic variation of clinical isolates. In epidemiological studies, PFGE is used for the determination of the overall genotype of the isolates. Serotyping and the determination of ptxS1 and prn alleles provide information about the expression and polymorphism of these virulence factors at a singlegene level. To date, the only way to determine alleles encoding for important antigens has been PCR-based sequencing, a relatively time-consuming and expensive method. Thus, new simple methods suitable for large-scale screening of isolates are needed. Recently, real-time PCR using fluorescent-labeled hybridization probes has been applied to the determination of prn and ptxS1 alleles of B. pertussis 24,25 These assays proved a good alternative to sequencing as they correctly identified...

Serologic Relationships and Variability

Polyclonal sera fail to distinguish in the virus neutralization test between any of the isolates of capripoxvirus so far examined. Sheep, goats, or cattle that have been infected with any ofthe isolates are totally resistant to challenge with any ofthe other isolates. On this basis, it has been possible to use the same vaccine strain to protect all three species. No monoclonal antibodies are as yet available against capripoxvirus, but it can be expected that differences will emerge between strains using these reagents.

Properties of the Virion

Pooled human y globulin, which has a respectable titer of antibodies to CMV, has been in use as a prophylactic therapy in transplant settings to reduce the incidence of CMV disease alone and in combination with antiviral compounds. Monoclonal antibodies that have a strong neutralizing capability have been tested but have thus far failed to show the benefit ascribed to human y globulin. Vaccines for CMV were initially developed in the 1970s, and one, Towne 125, has undergone almost continuous evaluation since its initial characterization. This vaccine induces cell-mediated and humoral immunity to CMV, and, when evaluated in a solid organ transplant setting, was attributed with reduction in disease severity. Due to the fact that immunity induced by Towne 125 is not as strong as that induced by natural infection, recombinant chimeric viruses that combine segments of the Towne vaccine genome and a low passage strain, Toledo, have been made to test for immuno-genicity. Vaccines consisting...

Dl Particles in Natural Infections

DI RNAs are identified in stool and blood samples of humans suffering from hepatitis A virus, an infection known to be rather moderate and prolonged. DI particles are identified in measles virus-attenuated vaccine preparations which have been, and are being, widely and successfully used (raising the question of DI particle participation in vaccine attenuation). Measles viruses defective in viral assembly are currently found associated with human subacute sclerosing panencephalitis (SSPE). The brain cells of SSPE patients were, moreover, shown to harbor many species of measles virus copy-back DI RNAs. Direct amplification of a portion of the HIV tat gene from infected patients demonstrates that about a third of the sequences correspond to defective

Serological Relationships and Variability

For epidemiological studies and vaccine strain selection, the serological relationships between field virus isolates or laboratory strains are expressed as r values, that is, the ratio of the neutralizing titers of immune sera against heterolo-gous and homologous viruses. The serological relationships between virus isolates are frequently nonreciprocal, showing that closely related viruses may induce broadly cross-reactive or narrowly specific immune responses. Complement fixation assay and enzyme-linked immunosorbent assay (ELISA) using polyclonal sera or monoclonal antibodies are also used for epidemiological studies.

Host Range and Virus Propagation

FIV has limited host range in that productive infection is found only in felid species. Domestic FIV has been found in the wild cat population, Tsushima cat (Felis bengalensis euptilura), and may present problems to the conservation of this endangered species. In domestic cats, FIV infects macrophages, endothelial cells, B cells, and CD4+ T cells as well as CD8+ T cells. In addition, FIV has been shown in vitro to infect feline astrocytes and fibroblastic Crandell feline kidney cells (CrFK). Defective infection of a human cell line has been reported however, there has been no evidence of zoonotic transmission and infection of humans with FIV. As with HIV, propagation of FIV in culture will rapidly adapt the virus and appears to alter the tissue tropism. Thus, the use of laboratory strains for vaccine challenge has been criticized and challenge inocula from in vivo sources have been recommended.

Virion Structure and Properties

PV virions form a nonenveloped, icosahedral structure of 55-60 nm diameter (see Figure 4). The capsid is composed of the major capsid protein, L1, and the minor capsid protein, L2, which form 72 pentameric capsomeres with an icosahedral symmetry of T 7. The viral genome is packed in a nucleohistone complex. The L1 protein can self-assemble into virus-like particles (VLPs) VLPs present the conformational epitopes required for generating high-titer neutralizing antibodies and are the basis of very successful vaccines in humans and animals.

Notable Animal Papillomaviruses

Cottontail rabbit papillomavirus (CRPV) naturally infects the cutaneous epithelium of wild cottontail rabbits and is also able to infect jackrabbits and snow-shoe rabbits. In contrast, experimental infection ofdomestic rabbits results in nonproductive papillomas that support normal early viral gene expression and genome replication, but are unable to support late gene expression and virus particle production. CRPV-induced papillomas can either persist or regress, depending on host genetic factors, and persistent papillomas can progress to carcinomas in both wild and domestic rabbits. CRPV DNA can induce papillomas on scarified rabbit skin and this has allowed a genetic assessment of which viral functions are required to induce papillomas. The CRPV model has also been used for the development of preventive and therapeutic PV vaccines. neous immune-mediated regression. COPV is a good model for mucosal PV infection and has been very useful in studying the immune response and the...

Functions of Papillomavirus Proteins

Sids in the absence of viral DNA or any other viral protein. This property has led to the production of HPV-6, HPV-11, HPV-16, and HPV-18 particles in het-erologous expression systems as prophylactic anti-HPV vaccines. The L1 protein is central to the first step of PV infections by binding to proteoglycans and integrins at the surface of epithelial target cells. The infection does not select specific target cells, and the epithelial specificity of PV infections is established by the transcriptional environment in epithelial cells.

Geographic Distribution

Foot-and-mouth disease occurs widely and is endemic in many countries, especially in tropical regions (Fig. 2). North America, Australia, New Zealand and Japan are free of the disease and maintain this status by rigorous application of import controls and quarantine. Mass vaccination campaigns have virtually eliminated the virus from some areas, e.g. Europe, but have been less effective in others, owing largely to logistical problems of vaccine distribution and the techniques of animal husbandry employed. Of the seven serotypes of the virus, serotypes A, O and C are the most widely distributed while serotypes SAT1, 2 and 3 are confined to the African continent and Asia 1 is only found in Asia.

Epidemiology and Control

To reduce disease prevalence, vaccination with live-attenuated or inactivated vaccines has also been used. However, vaccination does not result in sterile immunity, and vaccinated animals may still be infected with and carry the virus, and these carriers are no longer identifiable by serological analysis. This problem has been solved by the advent of the so-called 'marker' vaccines. This novel concept provided a breakthrough in animal disease control, and serves as a blueprint for control of other infectious diseases. It was based on the finding that several immunogenic envelope glycoproteins of PrV, such as gC, gE, and gG (see above), are not required for productive replication and can be deleted from the viral genome without abolishing virus replication. These gene-deleted strains can be produced easily in conven tional cell systems and can be administered as inactivated or modified-live vaccines. In fact, gene-deleted PrV strains were the first genetically engineered live-virus...

Prevention and Control of Infection

Because HDV infection is dependent on a concomitant HBV infection, control of HDV infection is best achieved by HBV vaccination. However, there is no effective measure to prevent HDV infection of chronic HBV carriers. No routine blood screening for HDV is currently performed however, HDV infection by contaminated blood sources can be prevented by screening for HBV. Currently, there is no specific treatment for delta hepatitis. Interferon a has been tried therapeutically with only marginal and transient effects. Ribavirin has been shown to inhibit HDV RNA replication in tissue culture.

Future Trends in Research on HSV

HSV possesses a number of features that will make it a continuing research model in the future. Among the most obvious are the following. (1) The neurotropism of the virus, along with the relative convenience of generating recombinants containing foreign genes expressed either under homologous or heterologous promoters, recommends HSV as a vector for introducing specific genes into neural tissue. This facility is increased by the fact that the viral genome can enter and be maintained in neural tissue in the complete absence of lytic phase viral gene expression. (2) The fact that HSV's replication is restricted in terminally differentiated neurons suggests its potential as a therapeutic agent against neural tumors, provided appropriate mutants can be constructed. (3) The benign nature of normal infection with HSV also suggests its potential use as a vaccine vector by incorporation of specific antigens into the viral

Primary Nursing Diagnosis

Immune globulin (IG) can provide protection against clinically apparent HAV. IG should be given to household contacts of patients with HAV and to persons who plan to travel on prolonged visits to third world countries or other places where sanitation is poor. It may also be given to people with exposure to HCV and HEV, but its effectiveness for these two types is uncertain. Hepatitis B immune globulin (HBIG) should be given to persons with exposure to hepatitis B surface antigen-positive blood, including accidental needle sticks. Vaccination against HBV is

HIV Cellmediated Immunity

Infection with HIV poses a particular problem for immunity for two reasons. The first is that the viral coat glycoproteins vary greatly, which limits the effectiveness of vaccines depending on the presence of pre-existing neutralizing antibody. The second is that the cell surface receptor for HIV is the CD4 molecule expressed on the helper T cell and, in humans, on some macrophages. Chemokine receptors have recently been identified as coreceptors for HIV infection. The development of the acquired immune deficiency syndrome (AIDS) is associated with the progressive, inexorable loss of the CD4+T cells. At least part of this may reflect elimination of the infected CD4+T cells by the virus-specific CD8+T cells, which remain fully functional CTL effectors during the course of this persistent infection. Also, stimulation of the CD4+T cells activates the virus growth cycle and thereby increases viral load. A further complicating factor is that virus reservoirs persist in association with...

History or How We Got to Where We

The first vaccine, introduced for smallpox by Jenner (1798), depends on CMI effector mechanisms. Systematic analysis of the ectomelia (mousepox) model by Fenner (1947) set the stage for modern studies of CMI, with Blanden showing some years later (1970) that primed Thy-1+ cells promote virus clearance. Recombinant poxvirus (vaccinia) tech nology has also been used very effectively for the identification of the antigenic proteins peptides involved in virus-specific T cell recognition. This approach (pioneered by Paoletti and Moss) has led to practical consequences, for example the recombinant rabies vaccine developed by Koprowski and his colleagues for use with feral populations. See also Autoimmunity Cytomegaloviruses (Herpesviridae) Animal cytomegaloviruses, General features (human), Molecular biology (human), Murine cytomegaloviruses Epstein-Barr virus (Herpesviridae) General features, Molecular biology Human immunodeficiency viruses (Retro-viridae) Molecular biology,...

Structure of the Hemagglutinin HA

In type A influenza virus, the HA accounts for about 25 of the viral protein. It is responsible for the attachment of virus to cells and for the penetration of the virus into the cell during the initial stages of infection. Antibodies to the HA neutralize the infectivity of the virus. Variation in the HA glycoprotein is mainly responsible for the continually occurring outbreaks of influenza and for our inability to control these by vaccination.

Detailed Consideration of Dominantnegative Mutants

Live virus vaccines should contain dominant negative mutations In this connection it should be noted that the ability to interfere with the growth of wild-type virus would be a particularly desirable trait in the case of live virus vaccines. The use of vaccine viruses with attenuating mutations that also confer a dominant-negative phenotype would add a significant degree of protection against virulent revertants that may arise during the immunizing infection or against epidemic viruses that may be circulating concurrently in the population. In addition to their immunizing potential, dominant-negative vaccine viruses could offer short-term antiviral protection until the immune response to the virus is firmly established. Whitaker-Dowling P, Maassab HF and Youngner JS (1991) Dominant-negative mutants as antiviral agents simultaneous infection with the cold-adapted live-virus vaccine for influenza A protects ferrets from disease produced by wild-type influenza A. J. Infect. Dis. 164 1200.

Evolution and Genetics

Serological investigations have demonstrated that sera collected from individuals prior to the use of SV40-contaminated polio and adenovirus vaccines contained antibodies to JCV and BKV. This finding eliminated any suspicion that the high prevalence of anti-JCV and anti-BKV antibodies in today's population is due to exposure to SV40 in vaccines. Based on the extent to which the human and monkey viruses have diverged, it is evident that the viruses have not recently evolved from one another.

Avian Influenza in Thailand

Thailand first recognized the massive die-offs of poultry by late 2003, and the government officially reported the outbreak of H5N1 pathogenic influenza virus on January 23, 2004. At present, the country had already passed three waves of the epidemics. Outbreaks mostly occurred in the central and eastern parts of the country where water reservoirs and wetlands are abundant and poultry population is dense. The outbreaks also happened when the weather was wet and cool. Poultry vaccination is prohibited in Thailand. Pre-emptive depopulation and several means of biosecurity measures have been applied to control the outbreaks. Free-grazing ducks, fighting cocks and backyard chickens remain to be the major problems of the country. Of all three outbreaks, there were 22 human cases with 14 deaths which made the fatality rate 63.6 . The disease was more fatal in children than adults. The infection also spread to other mammalian species tigers, leopards and cats. Phylogenetic analysis revealed...

Geographic and Seasonal Distribution

Assumed to be similar to that for measles virus (approximately 250 000) but no systematic study has been undertaken to ascertain this for mumps virus. Before successful control of mumps by vaccination had been achieved, outbreaks of mumps were more often observed in the winter and spring than in the summer, at least in the temperate northern hemisphere, but this seasonal pattern was not observed in the tropics.

Clinical Features of Infection

Bluetongue in sheep is characterized by a rise in body temperature, which may last for up to 14 days, accompanied by an increase in respiration rate. Edema and inflammation around the face, mouth and nose are often observed, accompanied by hemorrhages in the mucous membranes of the mouth, which range from petecheal to ecchymotic. In a few cases the tongue becomes swollen, markedly congested and may protrude from the mouth. Although this feature of infection is transitory, the cyanotic appearance of the tongue in such cases gave rise to the name for the disease. The epithelial lesions of the mouth may become chronic and ulcerated, resulting in bacterial infection and necrosis. Coronitis or inflammation and degeneration of skeletal muscles can result in lameness and an unwillingness or inability to stand. Vomiting may result from smooth muscle lesions of the esophagus and pharynx, leading to pneumonia, which is frequently fatal. Other features include hemorrhages at the skin-horn...

Pathology and Histopathology

In sheep the replication of BTV takes place in hemopoietic and lymphoid tissues, including the spleen, bone marrow, monocytes, macrophages, neutrophils, vascular endothelial cells and draining lymphoid tissues. Lesions in acute infections are caused primarily by vascular thrombosis occurring in the capillaries and small blood vessels, resulting in hemorrhage and edema within the surrounding tissues. In the squamous layers of the skin and mucosa, vacuolation and necrosis of the epithelial cells can result, developing into erosions and ulcerated areas in more chronic cases. Skeletal muscle degeneration is frequently seen as focal areas within the muscle mass, associated with hemorrhages and edema. Lesions have been described in many other organs and appear to relate primarily to breakdown in the microvasculature, resulting in thrombosis, hemorrhage, edema, ischemia and necrosis of surrounding tissues. Affected organs include the heart, lungs, spleen, thymus, kidneys, skeletal muscles...

Parapoxviruses iPoxviridae

The ability to generate VLPs has revolutionized papillomavirus research. These VLPs are very useful for serological studies and have been the basis of very successful prophylactic vaccines in cattle, dogs and rabbits. These animal systems should also prove useful for developing efficient therapeutic vaccines and for testing antiviral drugs that may be used in treatment of PV infections in humans.

Commercial Application

Transgenic microbes have many commercial and practical applications, including the production of mammalian products. A company called Genentech was among the earliest and most successful commercial enterprises to use genetically engineered bacteria to produce human proteins. Their first product was human insulin produced by genetically engineered Escherichia coli. A variety of other human hormones, blood proteins, and immune modulators are now produced in a similar fashion, in addition to vaccines for such infectious agents as hepatitis B virus and measles.

Properties of Virion and Proteins

A better understanding about their replication and host-virus interactions is essential in order to combat the diseases caused by them. Progress in the basic knowledge of parainfluenza viruses was stymied due to constraints on the manipulation of negative-sense virus genome. With the success of reverse genetics for manipulation of these viruses, a surge of knowledge is expected. This approach will be helpful in the in-depth understanding of the replication strategies of parainfluenza viruses and in designing efficient antivirals and vaccines against them.

Pathogenicity CPV and FPV

The viral factors that result in attenuation of the viruses have not been defined, and the pathobiological basis of the attenuated phenotype is not known. However, some attenuated CPV vaccine viruses are shed at lower titers in the feces, suggesting a reduced replication in the intestinal epithelial cells.

Genetics and Evolution

Regarding virus evolution, interest has been generated with respect to three closely related viruses, FPV, MEV and CPV. Infection by feline parvovirus has been recognized for more than 100 years. Mink enteritis virus was recognized by the middle of the twentieth century ( 1950) and, more recently, CPV (a 'new' dog parvovirus) was recognized in the 1970s. It is believed that CPV evolved from FPV. One hypothesis has suggested that CPV evolved from vaccine strains of FPV, while more recently it has been suggested that the canine virus moved from cats to dogs via an intermediate host such as the fox. Although DNA viruses mutate at a much slower rate than RNA viruses, changes do occur. Studies to map the residues critical to determining the host range of CPV indicate that a very few key amino acid changes in the major capsid protein VP2 are responsible. Similar results have been obtained for MVMp and MVMi, as well as two strains of PPV. MVMp replicates in mouse fibroblasts MVMi replicates...

Agricultural Applications

One approach to improving the economic value of crops is to give them traits that are completely new for that plant. Some crops, including potatoes, tomatoes, and bananas, have been engineered with genes from pathogenic organisms. This is done to make animals, including humans, that eat the crops immune to the diseases caused by the pathogens. The genes code for proteins that act as antigens to induce immunity. Thus edible parts of plants are engineered to act as oral vaccines. This approach may be particularly effective for pathogens, such as those causing diarrhea and other gastrointestinal disorders, that enter the body through mucous membranes. This is because the medicine in the food comes into direct contact with these membranes and does not have to be absorbed into the blood stream. Genes have also been engineered into crop

Immune Response and Prevention

Viral strains that do not produce viremia can often be used as live vaccines. The NADL2 strain of PPV, but also others such as the HT strain of PPV (no viremia), can be used. Some workers have been able to induce high antibody titers to PPV with inactivated virus. An early management method for PPV was the back-feeding of fecal material or fetal tissues from PPV-infected sows. Infections with BPV are widespread and are clinically inapparent in adults. BPV vaccines are not yet available nor has the need for vaccination been demonstrated.

Challenges for the Future

Prophylactic vaccines have proven to be very effective against acute infections such as polio, measles, mumps, rubella and smallpox. There is also a very effective prophylactic vaccine for HBV, a normally chronic infection. This vaccine, based on HBV surface antigen, does not work therapeutically for individuals with established HBV infections. The lack of an effective treatment to eliminate pre-existing persistent infections represents a significant gap in the physician's arsenal of weapons against viral infections. Treatment strategies targeting antigen presentation by dendritic cells may also prove helpful. Candidate vaccines, drugs, or combination treatments for the elimination of established chronic viral infections will need to be as sophisticated as the viruses themselves by allowing for countermeasures to T cell suppression, cytokine function suppression and latency. Until treatments for established persistent viral infections exist, these pathogens will continue to present a...

Taxonomy and Classification

The prefix 'yata' is a contraction from the names of the two recognized members of the yatapoxviruses yaba monkey tumor virus and tanapox virus. The members of the yata-poxviruses are closely related by sequence similarity, serol-ogy, and immunodiffusion tests. This genus is comprised of only two recognized members (YMTV and TPV) that so far have only been shown to infect primates, including humans. The members of this genus are immunologically distinct from members of the seven other Chordopoxvirinae genera. Vaccination by poxviruses from other genera, including vaccinia virus, will not protect from infection by the yatapoxviruses and, conversely, a previous infection with a yatapoxvirus will not block other poxvirus infections.

Characterization Of Meningococci

Effective public health countermeasures against menin-gococcal disease, such as vaccination programs, rely on the identification of meningococci, the ability to track temporal and geographical spread of meningococci, and the ability to relate locally and globally obtained isolates.1-11-1 Furthermore, characterization of the genetic diversity of meningococcal isolate collections has provided insights into the structure of meningococcal populations, and the evolutionary mechanisms that shape them.1-12-1 A range of techniques have been used to characterize meningococci, including differences in the electrophoretic mobility of cytosolic enzymes or the DNA sequence diversity of the meningococcal genome. However, methods relying on differences in the immunological reactivity of cell surface components are in most widespread use (Fig. 1).

Virus Propagation

Avipoxviruses replicate only in avian cells replication in mammalian cells is abortive and no infectious progeny are produced. Some vaccine strains of FWPV, such as the Cyanamid Webster FPV-M vaccine, even display a preference for chick embryo skin cells (CESs) over chick embryo fibroblast cells (CEFs). FWPV FP9 has been effectively adapted to CEFs but it displays a distinct preference for primary as opposed to secondary CEFs. Plaques on CEFs are not lytic, but the cytopathic effects manifest as changes in cell morphology, resulting in areas of altered refractive index with the plaques best viewed by dark field illumination. FWPV fails to plaque and replicates poorly in the recently derived chicken fibroblast cell line, DF-1. Replication is similarly poor in the chemically transformed cell line OU-2. It can be plaqued and replicated quite efficiently in quail cell lines, such as QT-35, but the presence in these cells ofviable endogenous Marek's disease virus (a herpesvirus) means that...

Prevention and Control of Poliomyelitis

Whereas passive immunoglobulin confers short-lived protection from disease, strategies for the prevention and control of poliomyelitis depend on the use of vaccines either based on the formalin-killed preparations developed by Salk or the live attenuated strains developed by Sabin. No antiviral chemotherapy is available. Vaccine viruses are grown in susceptible cells, usually primary monkey kidney cells or human diploid cells. Modern Salk-type vaccines are of far greater potency and quality than those manufactured in the 1950s and are currently prepared by concentrating, purifying and filtering the harvest to remove aggregates, then treating with 3 mM formaldehyde at 37 C for 2 weeks, before a second filtration step. The prolonged and slow inactivation method conserves the antigenic properties of the virus and the filtration steps remove aggregates which may protect virus from the formalin and therefore contain live virus particles. Such infectious aggregates are believed to have been...

Concluding Remarks

Poliovirus is a virus with a brilliant past and a fascinating presence, but with no future. Poliovirus, the etiologic agent of poliomyelitis, was one of the most feared and, therefore, is one of the most thoroughly studied infectious agents today. Ninety years of investigations of poliovirus biology and pathology have unraveled numerous secrets in virology and cell biology. These efforts produced two superb vaccines that, as a triumph of medical research, will ultimately lead to a global eradication of poliovirus.

Replication And Infectivity

Vaccinia virus has no definitive host, but it has been isolated from camels, buffalos, cows, pigs, and rabbits. 2 Vaccinia has been used in humans as a vaccine against smallpox infections because it produces mild, localized infections however, it can also induce life-threatening complications in immune-compromised individuals.1-3-1 Cowpox virus is probably maintained in rodent reservoirs in nature, but can occasionally infect humans, elephants, cattle, cheetahs, cats, and other animals. 2 Human infections with cowpox were known for centuries, but have been brought to public attention since the early vaccination attempts by Edward Jenner. Although most

Host Response to Infection

There are no detailed studies of the immune response of finfish to infection by aquareoviruses but, from observations that have been reported, it is clear that cellular and humoral immune reactions are stimulated. While not consistent, local infiltration of host inflammatory cells, particularly in the liver of infected fish, has been observed during aquareovirus infections. Moreover, in studies in which sera have been collected from infected fish, specific neutralization titers of > 1 4000 have been obtained in neutralization tests. Further evidence of an immune response comes from studies with a vaccine produced in China for use against GCRV. A crude inactivated GCRV vaccine was produced in the late 1970s and was reported to provide good protection (70 survival of fingerlings).

Diagnosis and Disease Management

Apart from the GCRV vaccine, no vaccines or therapeutics are currently available for the control of diseases associated with aquareovirus infections. As for other viral diseases of aquatic animals, avoidance is the preferred strategy. Thus, when available, pathogen exclusion can be attempted using good biosecurity and sanitary protocols in hatcheries and on farms. These can include the selection of specific pathogen-free (SPF) broodstock using virus isolation on cell lines and RT-PCR as screening tools, disinfection of fertilized eggs, and rearing water with, for example, ozone. In addition, stress reduction by maintaining high water quality and low stocking density is important. As aquareoviruses appear to have broad host and geographical ranges, the farming of aquatic animals where they are exposed to wild host species could present risks. Vaccines, when available, are likely to provide an additional level of protection.

Virus Propagation in Whole Organisms

Furthermore, fertilized hen eggs can be infected after several days of incubation (depending on the stage of embryonic development required). Most viruses can be grown in the embryonic membranes of fertilized eggs, i.e. the yolk sac (e.g. herpesviruses), the chorion (e.g. poxviruses), the allantois (e.g. influenza virus) and the amnion (e.g. mumps virus). Although laboratory animals or embryonated eggs are still the most appropriate propagation systems for some viruses (animals for arboviruses, coxsackieviruses and rabies virus eggs for orthomyxoviruses), they tend to be replaced by cell cultures, which are much more convenient to handle. For present-day virology, the use of animals is restricted mostly to research on viral pathogenesis and for production of vaccines.

Control and Prevention

The poor immunogenicity of inactivated CCV and KHV preparations suggests that the use of live, attenuated viruses is likely to be more effective in vaccination strategies. However, given the potential for latent vaccine virus to revert to wild type, thorough characterization ofvaccine candidates and development of assays to differentiate vaccine from wild-type virus are essential (for a precedent in higher vertebrate herpesviruses, consider pseudorabies virus). The use of avirulent strains of virus in which virulence genes are replaced by detection markers may lead in the long term to safe, efficacious vaccines. DNA vaccines also hold promise in combating fish her-pesvirus diseases, particularly in their avoidance of utilizing intact virus. From seven CCV genes tested, ORF59 (encoding the major envelope glycoprotein) and ORF6 (encoding a predicted membrane protein) produced significant resistance to challenge, with combined vaccination even more effective.

Prevention and Control of Rabies

Rabies may be controlled at three levels human, domestic animal and wild animal. Until widespread canine vaccination programs were initiated in the late 1940s rabies was controlled only at the human level, with hundreds of thousands of persons vaccinated world-wide for exposure to rabid animals, mostly dogs. Rabies in dogs was controlled when potent animal vaccines became available (especially after the advent of proper vaccine potency tests) along with effective dog vaccination programs (those resulting in the immunization of at least 70 of community dogs) and stray dog control. This stopped dog-to-dog rabies transmission as well as serving as a barrier between infected wild animals and human populations. Re cently an additional step has been taken involving the oral rabies vaccination of wild animals (foxes, raccoons) to eliminate rabies in those populations.

Prevention and Control of Disease Caused by Rabiesrelated Viruses

Prevention of human infection with rabies-related viruses is based on elimination of exposure in Europe and Africa, contact with bats should be avoided. Sick animals or those with abnormal behavior should be handled only with protective gloves. There is no vaccine available for Mokola or Lagos bat viruses. Commercial rabies vaccine and immune globulin may give limited protection against Duvenhage and EBL infection. Thus persons with bat bites and other bat exposures should receive classic rabies postexposure treatment, but should not expect complete protection. Persons whose occupations lead to exposure to bats should receive pre-exposure rabies vaccination. Vaccines prepared from Mokola, Duvenhage and European bat lyssaviruses would be useful biologi-cals, but with the very low attack rates, it is not likely that such vaccines will be developed commercially.

Fish Rhabdovirus Detection and Control

Research on vaccines to protect fish from rhabdovirus infections has been conducted for more than 30 years. Initially, this work focused on traditional approaches including inactivated viruses or live-modified vaccines. Later, recombinant DNA technology produced experimental vaccines using bacterial or baculovirus expression systems as well as peptide immunogens. While some of these traditional and molecular vaccines were reported to be highly efficacious in both laboratory and field trials, prohibitive development and licensing costs, inconsistent efficacy, or safety concerns have prevented their use on a commercial scale. More recently, DNA vaccines have been engineered for protecting fish against the novirhabdo-viruses, IHNV, VHSV, and HIRRV. These vaccines have been studied extensively and show exceptionally high efficacy against severe viral challenges under a wide range of conditions. An IHNV DNA vaccine was licensed for use in Canada in 2005. With regulatory concerns and...

Emerging Technologies

In addition to recombinant proteins and monoclonal antibodies, recent advances have led to a plethora of new technologies such as antisense oligonucleotides, gene therapy and therapeutic vaccines. The mechanism of action of the drug candidates resulting from these technologies pose unique challenges in drug delivery often requiring novel formulations optimized for penetration of the cell wall and resistance to intracellular components. While many of these challenges are being addressed via conventional drug delivery systems by incorporation of the active drug into structures such as liposomes, a new arena of novel drug delivery systems, such as virus mediated cell penetration agents, have emerged to address some of the unique delivery requirements of these novel biomolecules. As these technologies mature to generate viable candidates for drug development, there will arise a need to characterize these novel therapeutic agents in complicated drug delivery systems. In addition, the...

Immunoprophylaxis and Treatment

Because natural RSV infection does not provide complete, long-lasting resistance to reinfection, it seems unlikely that a vaccine will do so. None the less, early immunization could reduce the incidence of serious disease associated with the first one or two infections of life. It is likely that natural infections would not be prevented, but their consequences would be reduced in severity and would have the desirable effect of boosting immunity. Very young infants, who would be the targets for immunization, have been shown to have reduced immune responses to RSV infection owing to immunologic immaturity. Also, maternally-derived serum antibodies can suppress the induction of antibodies and CTLs, although this effect can be abrogated to a considerable extent by direct immunization of the respiratory tract. Recent vaccine trials suggest that very young infants can mount a satisfactory immune response against live attenuated RSV administered intranasally. Vaccine safety is a major...

Laboratory Diagnosis

Most of the known respiratory viruses can quite readily be cultivated in appropriate cell lines from the corresponding host species, e.g. diploid lung fibroblasts or HUT-292 cells for human viruses. Growth of the virus is detected by cytopathic effects and or hemadsorption or immunofluorescence, and the virus recovered from the supernatant is then typed using any of a variety of serological techniques. However, this sequence is so time consuming and expensive that isolation and identification of virus is today undertaken mainly by reference laboratories requiring a large supply of the virus for further characterization, for research, or for antigen or vaccine production. Viral culture nevertheless remains a vital first step in the identification of agents responsible for newly emerging diseases.

Transmission Diagnosis Prevention and Control

Despite the fact that RE viruses are widespread in commercial poultry flocks, they do not create a real economical problem. However, the contamination of vaccines against Marek's disease virus (MDV) by RE viruses has been associated with a runting disease and chronic neoplasia. In addition, occasional outbreaks of neoplastic diseases in turkeys have also been described. RE virus epidemics are prevented by testing commercial vaccines for contamination by these A commercial vaccine is not available since RE viruses do not create a significant economic impact. It is, however, feasible to develop an effective vaccine against RE viruses. Fowlpox virus recombinants expressing the env gene of SNV induce neutralizing antibodies and reduce the viremia and runting disease in infected chickens.

Immune Response Prevention and Control

Due to lack ofstandardized molecular and experimental tools in fish, detailed knowledge of immune responses to viral agents is limited. This represents a major problem for the development of effective vaccines against fish viral diseases. For ISA, the ability to induce a strong lymphocyte prolifera-tive response correlates with survival and virus clearance, while induction of a humoral response is less protective, as shown in experimental trials using MHC-compatible fish. Currently available vaccines against ISA contain inactivated whole virus grown in cell culture added to mineral oil adjuvants. Vaccines are approved by the United States Department of Agriculture (USDA) and the Canadian Food Inspection Agency (CFIA) and are commercially available in Canada and the USA. Vaccination has also been used in the Faroe Islands. The use of vaccines against ISA in the rest of Europe is subject to EU European Fair Trade Association approval. The present policy is that control of ISA should...

NOC Knowledge Treatment Regimen

Inform parents as to the benefits of routine immunizations with H. influenzae (type B) vaccine, beginning at 2 months of age for a total of 3 doses. suggests the incidence of this form of meningitis has decreased since the vaccine was introduced may decrease the spread of infection to unvaccinated infants.

Assessment Of In Vivo Cytotoxicity By Flow Cytometry

Mice are immunized with DCs transduced with amplicon carrying the gene for the rabies glycoprotein and boosted with a commercial vaccine 4 days prior to being infused with a mixture of 2.5 x 107 target cells consisting of uninfected targets, DiOC18(3)-labeled at a low concentration, and target cells infected with the rabies virus, labeled at a high concentration. After 24 hr, mice are bled and cells are evaluated by flow cytometry (Fig. 9.17.6). It is expected that the mice primed by DCs transduced with the amplicon rabies can generate a CTL activity that destroys targets infected with the rabies virus while leaving the uninfected targets.

Animal models to understand the role of cytokines in htlv1 pathogenesis

Since the initial discovery of the virus, a variety of animal models of HTLV-1 infection have been reported. However, the virus consistently infects only rabbits (100,101), some nonhuman primates (102,103), and to a lesser extent rats (104,105). Viral transmission in mice using typical methods of infection produces inconsistent infections and limited virus expression in tissues (50,106,107). Nonhuman primates have been infected with HTLV-1 and certain species have a natural infection with STLV-1 (108-111). The squirrel monkey has been successfully infected with HTLV-1 and offers an attraction nonhuman primate model of HTLV-1 for vaccine testing (112-114). Rats have been infected with HTLV-1 producing cells and offer a model of the neurologic disease associated with the viral infection (115-118). Rats have also been used to test the role of cell-mediated immunity to the infection (116,119). However, controversy exists regarding the reproducibility of the viral infection in rats (105)....

Control of Viral Diseases in Shrimp

As invertebrates, marine shrimp and freshwater prawns lack the acquired immune systems that exist in vertebrates. Consequently, a disease control based on vaccination cannot be used. Some antiviral defense reactions (innate immunity) have been reported in Crustacea but the mechanisms by which these occur are largely unknown and prevention appears as the most useful method for control. For this reason, specific and sensitive DNA-based tools for early detection are now available for most of the viral diseases. These tools allow selection of healthy broodstock and a good knowledge of the health status of postlarval seed introduced into ponds. The availability of these tools has also led to the estab

Transmission and Tissue Tropism

Morbillivirus transmission is by direct contact with secretions or excretions of infected animals. The morbilliviruses are highly contagious all discharges can carry the virus. However, since the virus is extremely sensitive to environmental factors, such as heat, sunlight and chemical inactivation, it requires close contact with an infected animal for successful transmission. It is therefore relatively easy to control by regulating animal movements, in conjunction with a strict quarantine and slaughter policy where necessary. Even without the availability of vaccines rinderpest was successfully controlled and eliminated from Europe by these means.

Prevention and Control of Rotavirus

Two avenues leading to prevention and control of rotavirus disease are vaccination and oral rehydration therapy. Treatment with oral rehydration solutions containing glucose and electrolytes is highly effective for ameliorating the consequences of rotavirus infection, but there are serious logistical, cultural and educational difficulties limiting the distribution of this treatment resource into underdeveloped areas. Recent evaluations of this approach in the USA suggest that it is underutilized even in a developed setting. Vaccination strategies that have been tested have utilized the host range restrictions of animal rotaviruses in a 'Jennerian' approach to disease prevention. For example, simian and bovine rotaviruses have been used as naturally attenuated vaccine strains in children. Field trials demonstrated these vaccines to be safe and immunogenic, and efficacy against severe disease was high in developed countries. Efficacy in underdeveloped countries has been more difficult...

Background Information

The relevance of cytokine measurements in different physiological and pathological conditions is currently well established. Cytokines play a crucial role in immune responses against infection and tumor cells, as well as in vaccination and transplantation, among other situations. Through complex networks, cytokines are essential elements in priming, amplifying, directing, or inhibiting specific immune responses (Arai et al., 1990). At present, several methods are available to measure blood cell responses based on cytokine production. Most of these methods use bulk assays that detect and or quantify specific cytokine mRNA and proteins. To measure mRNA, northern blot analysis, RT-PCR, and in situ hybridization techniques can be used. Despite their sensitivity, these approaches have several major limitations (1) in most instances they can not link cytokine responses to single cells (2) quantitation can be achieved only with some procedures

TVansmission and Tissue Ttopism

Rubella virus is transmitted between individuals by aerosolation. Congenitally infected infants shed virus for three to six months following birth and are a source of transmission. Although vaccine virus can be recovered from vaccinees, transmission of vaccine virus to susceptible individuals has not been observed. Reinfection with rubella virus does occur and is more frequent among vaccinees than naturally infected individuals due to lower antibody levels. Reinfection usually proceeds without viremia, clinical illness or virus shedding, however, reinfection with clinical illness has been reported. There are a small number of cases in which rubella virus reinfection of pregnant women with well-documented immunity has resulted in CRS.

Prevention and Control of Rubella

As discussed above, live attenuated vaccines were developed and placed in use by 1970. The vaccine used in most countries, with two exceptions, is the RA 27 3 vaccine. This vaccine was developed by multiple passaging of a virus isolate from an explant culture of a fetal human kidney in WI-38 human fetal diploid lung cells. Several of the passages were done at 30 C and limiting dilutions were used at some of the passages. Production of the vaccine is done in both WI-38 and MRC-5 diploid human cell cultures. In Japan, five attenuated vaccine strains were developed and are currently in use. Additionally, at least one Chinese vaccine strain is currently in use in China. Rubella attenuated vaccines cause subclinical infection with transient viremia in susceptible recipients. However, transmission of vaccine virus has not been reported. The RA27 3 vaccine strain produces seroconversion in greater than 95 of recipients. Vaccine-induced titers are lower than those induced by natural infection...

Henipaviruses New Threats for Southeast Asia and Australia

Hendra virus was first encountered in Brisbane, Australia in 1994 and subsequently in other more northerly parts of Queensland. Nipah virus was first encountered in northern Malaysia in 1998 but has subsequently been found in Singapore, Bangladesh, Cambodia, Thailand, Indonesia and India. It has been established that bats, particularly Pteropus species (fruit bats or flying foxes), act as the reservoir for both viruses with horses (Hendra virus) or pigs (Nipah virus) as intermediate hosts and humans as occasional victims. These closely related viruses form a new genus (Henipavirus) of the subfamily Paramyxoviriniae of the family Paramyxoviridiae. The morphology and genomic structure of these viruses have been established and their nucleoprotein, phosphoprotein, C protein, matrix protein and fusion protein have been characterised. Diagnosis of infection with Henipaviruses can be made by serology, molecular testing or culture. Human clinical illness consists of fever, encephalitis and...

Atc Ata Gtt Agt Agt

Although it was considered that rotaviruses were species-specific it is becoming increasingly apparent that this is not so. The simian rotavirus SA11 can be used to infect mice, and some human rotavirus vaccines are reassortants of bovine or simian rotaviruses with human rotavirus VP7. How frequently this occurs naturally is unclear and most often it is inferred by detecting an animal-specific VP4 or VP7 in a human rotavirus strain. Examples of this include G5 (pigs), G6, and G8 (cattle) rotaviruses, and, for example, G8 rotavirus makes up over 50 of the G types in Malawi and Nigeria. Analysis of the Malawian rotavirus VP7 gene indicated that it is most closely related to bovine strains A5 (93.6 identical) and Cody (92.3 ). In Nigeria a G8 cattle rotavirus isolate was found to be closely related to a human isolate in its VP7 (99.9 ) and by Northern blot where all 11 segments cohybridized. Interspecies transmission combined with genomic reas-sortment appears to be a powerful generator...

Treatment And Prevention

The mainstay of treatment is the assessment and degree of dehydration and appropriate rehydration as necessary. There are no antirotaviral drugs available but probiotics (Lactobacillus spp.) and oral pooled human immunoglob-ulin have been shown to decrease the frequency and duration of vomiting and diarrhea. 1 It is difficult to prevent transmission of rotavirus by simple hygienic measure, but in hospitals, children should be nursed in isolation or cohorted in rotavirus wards. Specific prevention by vaccine is possible as was demonstrated by the recently withdrawn live rhesus reassortant vaccine (containing G1-G4). It was one of the first rotavirus vaccines to be equally efficacious in infants in developing and developed countries. It was withdrawn from use because of concerns over its potential to cause intussusception. There are, however, a number of new candidate vaccines in production.

MCRPs and Adaptive Tcell Responses

The effect is factor D- and, at least in part, C5-dependent, indicating that local alternative pathway activation is essential. Furthermore, APCs deficient of CD55 produce more IL-12 and C5a and promote more IFN-y-producing T cells. This process is dependent on C5a receptor expressed on APCs. It appears that C5a release regulated by CD55 interacts with C5aR on APCs and regulate IL-12 production and T cell differentiation (Lalli et al. 2007). Studies from Song's group have shown that T cell recall responses using splenocytes from mice immunized with surrogate antigen ovalbumin (OVA) or an MHC class II restricted myelin oligodendrocyte glycoprotein (MOG)-derived peptide are more profound in CD55-deficient mice than in wildtype mice (Liu et al. 2005). T cells from CD55-deficient mice secrete more IFN-y and IL-2 upon antigen restimulation. This effect is dependent on a functional complement system since the enhanced cytokine release is abrogated in C3-deficient CD55-double deficient mice....

Applications of RNA Phages Three Hybrid Assay

A more medically orientated set of applications has also been developed. For instance, it is known that viruses present defined epitopes to the immune system of their hosts. If those epitopes are common and unchanging, the immune response that occurs after an initial infection will render the host immune to further infection by that particular virus. Many viruses however constantly alter their outer protein surfaces presenting differing epitopes to the immune system, thus escaping immune neutralization. However, modern structural immunology techniques can identify conserved functional domains sequences within these viral proteins that cannot be altered without also causing the virus to lose the ability to replicate or assemble. Raising immune responses against such refined constant epitopes leads to potent vaccines against a range of human and animal pathogens. In fact, work in this area has shown that the immune system is particularly well evolved to recognize repeated copies of...

Archaebacterial Membrane Lipids and Analogs

The potential applications of archaebacterial lipid liposomes (archaeosomes) as novel vaccine and drug delivery systems have been reviewed recently.88-90 In general, this type of liposomes exhibited higher stability to oxidation, high temperature, alkaline pH, and action of phopholipases. The safety profile study of these type of liposomes had shown that they are well tolerated after intravenous or oral delivery in mice. The stability and safety profile of these liposomes indicated that they may offer a superior alternative to the use of conventional liposomes.

Detection of Borreliacidal Antibodies by Flow Cytometry

Borreliacidal antibodies are lethal to the spirochete Borrelia burgdorferi, the causative agent of Lyme disease. Detection of borreliacidal antibodies is useful for serodiagnosing Lyme disease and monitoring immune status after vaccination. Their detection, however, is dependent on the use of live organisms. Visual assessment of cell viability or monitoring of pH-dependent color changes in growth medium can be used to identify killing by borreliacidal antibodies, but detection by flow cytometry significantly increases sensitivity by allowing evaluation of small numbers of organisms. In addition, data from multiple assays can be rapidly acquired and analyzed objectively.

Criteria for Causal Relationship between Virus and Cancer

The physical association of viral genes with tumor cells, in combination with data on oncogenic activity from cell culture or animal experiments, is usually regarded as a most convincing evidence for a role for a virus in human carcinogenesis however, even better proof of the effective contribution of the virus is obtained from longitudinal epidemiological studies. Finally, the most convincing argument in favor of a necessary role for a tumor virus will be cancer prevention by intervention directed at the virus, such as specific vaccination.

Protection Following Immunization by Different Routes

The area of mucosal surface in mammals is far greater than the area of skin, and many viruses infect via this route. The main sites of entry are oral, rectal, respiratory, urogenital and ocular. Following vaccination via a mucosal route such as the gut, the first line of defense is s.IgA, and the CMI responses originate from local lymphoid tissues such as the Peyer's patches. For example, OPV induces both a mucosal and systemic response whereas IPV induces only the latter which, however, is sufficient to prevent infection of the central nervous system and poliomyelitis. Measles vaccine is given parenterally viremia occurs so that some virus reaches the respiratory tract and a mucosal, as well as sytemic response, occurs. There is still interest in administering this vaccine intranasally to achieve a stronger mucosal response which might also be less affected by maternally derived antibody. There is a 'common mucosal system' so that an immune response induced say in the gut will cause...

Physical Properties

The development of a stable smallpox vaccine was greatly facilitated by the fact that the infectivity of vaccinia virus is relatively unaffected by environmental conditions which inactivate most other viruses. This property, together with the large particle size, was also the reason why vaccinia virus was the first animal virus to be purified extensively. Heating at 55 C for 60 min, or at 50 C for 90 min completely destroys infectivity. Other methods for destroying infectivity were tested in attempts to produce an inactivated smallpox vaccine. Ultraviolet irradiation, formaldehyde treatment, photodynamic inactivation with methylene blue and gamma irradiation were all found to inactivate vaccinia virus, but some of these procedures also resulted in a loss of antigenicity.

Posttranslational Processing

Poxvirus expression systems have been used to express hundreds of proteins of biological and medical importance. The practical application of vaccinia virus vaccine candidates has been demonstrated in both the veterinary and human fields. Vaccinia was used successfully as a vaccine for the eradication of smallpox. Other examples of its use include vaccinia virus recombinants to protect raccoons against rabies, a capripoxvirus vector to protect cattle against rinderpest, a swinepox vector to protect pigs against pseudorabies, and fowlpox vectors to protect chickens against influenza virus, Newcastle disease virus and infectious bursal virus. Clinical trials with a vaccinia-based HIV-l(IIIB) env recombinant have been initiated in the USA. Results from these studies clearly demonstrated the ability of this recombinant to prime an immunological response in the recipients, although the response was suboptimal in some individuals. A vaccinia virus-based vector expressing the Epstein-Barr...

Baculovirus Expression Vectors

Ally modify proteins correctly, there were concerns that they could not process high-mannose glycans like mammalian cells. However, recent reports on human plasminogen expressed in insect cells show that the enzymes necessary for processing high-mannose glycans can be activated with glycan processing identical to that found in the human-expressed protein. These are important considerations if baculovirus-expressed products are to have the same biological and immunological properties as that of the native protein. Baculovirus-expressed protein was used in the first human clinical trials for an acquired immune deficiency syndrome (AIDS) vaccine, using an HIV-1 (IIIB) env gene product purified from insect cells. Its general utility for production of purified proteins for clinical use remains to be demonstrated.

Modified LDL Antibodies and LDLContaining Immunocomplexes

The inverse correlations between modified LDL antibody levels and atherosclerosis, together with data obtained in laboratory animals suggesting that modified LDL antibodies are predominantly of the noninflammatory immunoglobin (Ig)M isotype (189) and human studies claiming that IgM antibodies to modified LDL may predominate over IgG antibodies (190) and have a protective effect in relation to the development of atherosclerosis (191) have led to considerable speculation, including the possibility of vaccination against atherosclerosis (192). This seems highly unwarranted, because of several other lines of evidence. First, the proposed protective murine IgM antibodies are predominantly reactive with oxidized phospholipids, although human antibodies reacting with modified lysine groups have been extensively characterized (193,194). Second, when the isotype distribution of modified LDL antibodies has been studied under stringent conditions, using affinity chromatography-purified...

Subjects for Further Investigation

These questions are all germane to the fact that an effective live attenuated vaccine strain (Oka) has been developed and is in widespread use in children in the industrialized world. However, the specific molecular nature of its attenuation is unknown. In recent studies in a SCID-hu model for VZV infection, it has been demonstrated that the Oka vaccine virus grows well in T-lymphocytes but not in skin cells, consistent with its antigenicity, as well as its relative inability to cause the typical varicella rash. In analogous experiments, VZV lacking gC has been shown to replicate poorly in skin cells, suggesting that this glycoprotein is a virulence factor for the virus. Now that we have a good animal model, as well as a reliable method for construction of viral mutants, we can anticipate substantial new data on VZV replication, both in vivo and in vitro.

RNA Virus Vector Systems

Researchers are investigating the potential of RNA genome-containing viral vectors, such as poliovirus, alphaviruses, influenza virus and vesicular stomatitis virus (VSV). These viruses have the potential advantage of not having a DNA phase in their replication cycle, which provides a measure of safety for their use in humans. Negative-strand viruses such as influenza and VSV do not undergo measurable rates of homologous RNA recombination, which contributes to the stability and safety of these vectors. Expression of foreign proteins has now been shown for vectors derived from influenza, rabies, VSV, respiratory syncytial virus, SV5 and Sendai virus. The foreign proteins include antigens derived from other viruses, bacteria and parasites, and in general have represented attempts to derive vaccines for agents for which no adequate vaccine currently exists. The vectors produced thus far have coded for a single antigen, and we can expect that in the near future vectors encoding multiple...

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