Risks connected with the use of conventional and genetically engineerd vaccines

Summary

A review is given of real and potential risks connected with the use of conventional and genetically engineered live and dead vaccines. Special attention is given to live carrier vaccines expressing one or more heterologous genes of other microorganisms. Because most carrier vaccines are still in an experimental phase, there is only limited experience with the risks of carrier vaccines. There are three potential risks of live carrier vaccines which will be discussed:

1. Changes in cell, tissue, of host tropism, and virulence of the carrier through the incorporation of foreign genes.

2. Exchange of genetic information with other vaccine or wild‐type strains of the carrier organism.

3. Spread in the environment.

Only limited experimental data are available on changes in biological behaviour of microorganisms through the incorporation of foreign genes. For example, there are indications that vaccinia virus carrying the attachment protein G of respiratory syncytial virus (RSV) replicates better in lungs of mice than vaccinia virus carrying other genes of RSV. Poxviruses carry genes that probably determine their replication in different hosts. Exchange of such host tropism genes might alter their host spectrum. Recombination between herpesvirus vaccine or wildtype strains may lead to the appearance of virulent strains with of without heterologous genes. Before carrier vaccines are applied, these risks must be thoroughly evaluated case‐by‐case. Potential methods for the design of safe carrier vaccines are discussed.

This article is based on a contribution to the course ‘Introduction of Genetically Modified Organisms into the Environment: Biosafety Aspects’, 4–14 December 1991, Wageningen, the Netherlands.     

Development and application of genetically engineered viral vaccines of poultry

Recombinant DNA techniques may completely revolutionize the way vaccines are developed and used. They offer potentially purer, safer, and greater efficacy than many currently used vaccines. This paper describes the various current approaches being used to develop recombinant vaccines. Genes are being cloned into bacteria, yeast, viruses, and eukaryotic cells. Synthetic polypeptides of specific epitopes are also covered. Scientific, practical, economic, and government approval to use recombinant vaccines in the field is also discussed.     

The impact of vaccines and the future of genetically modified poxvirus vaccines for poultry

The regular use of live or killed vaccines against infectious agents has remarkably improved the efficiency of poultry production. In some cases eradication of disease has been possible when the pathogen is antigenically stable and confined to a certain geographical area. In other instances monovalent or polyvalent live or killed vaccines have been effective in reducing mortality and morbidity. Many conventional vaccines are developed by trial and error and basic information about their genetic make-up is not known. While the poultry industry has benefited from the regular use of conventional vaccines, there is need for a new generation of effective vaccines that require minimal handling of birds during administration. Using molecular techniques, it is possible to identify the genes associated with virulence and protection. In genetically engineered vaccines, genes that encode protective antigens can be expressed in bacterial or viral vectors. In this regard, avianpox virus vectors appear to be promising for the generation of polyvalent vaccines expressing antigens from multiple pathogens.     

Risks associated with the use of herbs and other dietary supplements.

The use of dietary supplements (herbs, vitamins, minerals, amino acids, enzymes, and other compounds) is common in horses. They are heavily marketed in retail stores, magazines, and on the Internet. There is the perception that since these compounds are "natural" they are devoid of toxicity, and, therefore, they are safe to use. Some of the active compounds in supplements, however, have inherent toxicity, and using them may cause adverse effects. Even relatively non-toxic ingredients may be toxic if used over-zealously or for a long period of time. By and large, these compounds have not been tested for safety or efficacy when used as marketed, and, unfortunately, there is little regulatory oversight for such products. Other deleterious consequences of dietary supplement use include interaction of compounds in the products with conventional drugs, resulting in unexpected adverse effects, or the occurrence of violative residues in urine samples collected from show or performance horses. This article provides a brief overview of potential problems associated with dietary supplements, primarily focusing on products containing herbs and essential oils.     

Development of a genetically engineered vaccine against feline leukemia virus infection.

A genetically engineered subunit vaccine against FeLV infection was developed. The protective immunogen in the vaccine was a purified recombinant protein containing the entire amino acid sequence of FeLV subgroup A gp70 envelope protein. The optimal adjuvant was determined to be a highly purified saponin, QS-21, derived from Quillaja saponaria Molina. A vaccine formulation containing the recombinant protein, QS-21, and aluminum hydroxide was tested in specific-pathogen-free kittens and was shown to induce neutralizing antibodies as well as appreciable antibody responses to native gp70 by enzyme immunoassay and protein (western) immunoblot analysis and of whole virus preparations.     

Role of genetically engineered animals in future food production

Genetically engineered (GE) animals are likely to have an important role in the future in meeting the food demand of a burgeoning global population. There have already been many notable achievements using this technology in livestock, poultry and aquatic species. In particular, the use of RNA interference (RNAi) to produce virus‐resistant animals is a rapidly‐developing area of research. However, despite the promise of this technology, very few GE animals have been commercialised. This review aims to provide information so that veterinarians and animal health scientists are better able to participate in the debate on GE animals.     

猪细小病毒分子诊断技术与基因工程疫苗研究进展

猪细小病毒(PPV)最早是从培养细胞中发现并分离得到的一种小DNA病毒。研究表明,PPV不仅是引起母猪繁殖障碍的主要病原体之一,而且能够引起多种猪病。随着对猪细小病毒研究的不断深入,目前已经在病毒病原学、结构与非结构蛋白、感染机制、诊断与疫苗防制等方面取得很大进展。本文主要针对分子诊断新技术与基因工程疫苗防制等方面进行了阐述。     

Of mice and microflora: considerations for genetically engineered mice

The phenotype of genetically engineered mice is a combination of both genetic and environmental factors that include the microflora of the mouse. The impact a particular microbe has on a mouse reflects the host-microbe interaction within the context of the mouse genotype and environment. Although often considered a confounding variable, many host-microbe interactions have resulted in the generation of novel model systems and characterization of new microbial agents. Microbes associated with overt disease in mice have been the historical focus of the laboratory animal medical and pathology community and literature. The advent of genetic engineering and the complex of mouse models have revealed previously unknown or disregarded agents that now oblige the attention of the biomedical research community. The purpose of this article is to describe and illustrate how phenotypes can be affected by microflora by focusing on the infectious diseases present in genetically engineered mouse (GEM) colonies of our collective institutions and by reviewing important agents that are rarely seen in most research facilities today. The goal is to introduce the concept of the role of microflora on phenotypes and in translational research using GEM models.     

兔病毒性出血症基因工程疫苗的研究进展

兔病毒性出血症俗称兔瘟,它是由兔出血症病毒(Rabbit hemorrhagic disease virus,RHDV)引起的一种急性、烈性、高度接触性、致死性传染病。1984年中国首次报道了该病。RHDV曾是兔的一种毁灭性传染病,因给养兔业带来巨大的经济损失而备受养兔业的关注。1989年,世界动物卫生组织(OIE)将该病正式列为B类传染病,我国将其列为二类传染病。     

Morphological and immunohistochemical characterization of sarcomatous tumors in wild-type and genetically engineered mice

Malignant soft tissue tumors are commonly observed in wild-type and gene-targeted mice. These tumors have different degrees of differentiation, cellularity, cellular atypia, nuclear pleomorphism, normal and abnormal mitosis, and giant tumor cells with enlarged polylobulated nuclei. They are often diagnosed as pleomorphic sarcoma, undifferentiated sarcoma, fibrosarcoma, malignant fibrous histiocytoma, sarcoma, or sarcoma, not otherwise specified. Pleomorphic sarcomas have no morphological differentiation toward a differentiated mesenchymal or other tumor type in hematoxylin and eosin-stained sections. With the use of immunohistochemistry, human and mouse, tumors associated with these broad nonspecific diagnoses can often be demonstrated to be of a specific cellular lineage. With mouse models being used to delineate the molecular mechanisms, pathogenesis, and cellular origin of human sarcomas, it will be necessary to correlate the morphological and cellular lineage and the molecular profiles of the pleomorphic tumors associated with these mouse models. The results presented here show that with the use of immunohistochemistry, the cellular lineage of many mouse tumors with pleomorphic features can be determined.     

Early embryonic lethality in genetically engineered mice: diagnosis and phenotypic analysis

Embryonic lethality is a common phenotype that occurs in mice that are homozygous for genetically engineered mutations. These phenotypes highlight the time and place that a gene is first required during embryogenesis. Early embryonic lethality (ie, before and up to mid-gestation) can be straightforward to analyze because the stage at which death occurs suggests why an embryo has failed. Here we summarize general strategies for analyzing early embryonic lethal phenotypes in genetically engineered mouse mutants.     

Comparison of phytase from genetically engineered Aspergillus and canola in weanling pig diets

Ninety-six crossbred pigs with an average weight of 9.0 kg were used in a 5-wk trial to compare the efficacy of genetically engineered Aspergillus ficuum phytase, expressed in Aspergillus niger (Natuphos) or in canola seed (Phytaseed), for enhancing the utilization of phytate P in corn-soybean meal-based diets fed to young pigs and to evaluate the safety of Phytaseed phytase. Three levels of the two sources of phytase (250, 500, or 2,500 U/kg of diet) were added to a corn-soybean meal basal diet containing .35% total P, .09% available P, and .50% Ca. There were six pens per treatment (one barrow and one gilt/pen), except that the diet without added phytase was fed to 12 pens of pigs. Pen feed consumption and BW were recorded weekly. During wk 5, pen fecal samples were collected for determination of apparent digestibilities of DM, Ca, and P. At the end of wk 5, all barrows were killed, and the 10th rib on both sides was removed for determination of shear force and energy. Thirty pigs (six from the diet without added phytase and the diets with 500 and 2,500 U/kg phytase from both sources) were randomly selected for gross necropsy and histologic evaluation of liver, kidney, and bone tissues. Both sources of phytase were equally effective in increasing (P < .05) daily gain, gain:feed, apparent digestibilities of DM, P, and Ca, and 10th rib measurements. Fecal P excretion was reduced with phytase addition. Feed intake was increased by phytase levels during wk 4 to 5. No significant abnormalities were seen in any of the 30 pigs necropsied. The fit of a nonlinear function revealed that most measurements were reaching a plateau at 2,500 U/kg phytase. In summary, based on performance, bone measurements, and digestibilities of P, Ca, and DM of young pigs, the efficiency of Phytaseed was similar to that of Natuphos for enhancing the utilization of phytate P in corn-soybean meal-based diets. General necropsy and histologic examination of tissues indicated no toxic effect of phytase.     

The potential for liability in the use and misuse of veterinary vaccines.

The lack of specific rules regarding the use of animal vaccines by veterinarians leaves them vulnerable to legal action for negligence or breach of warranty. A veterinarian's liability may depend on the answers to the questions asked previously in this article. The answers ultimately depend on the specific circumstances of the case. Although no one can ensure that he or she is never going to be sued, veterinarians can go a long way in defending themselves against these kinds of allegations by conforming to the standards of practice as they apply to the care and use of vaccines; by adhering closely to the doctrines of informed consent; and by not providing undue warranty to the vaccine product he or she sells.     

Internet and print resources to facilitate pathology analysis when phenotyping genetically engineered rodents

Genetically engineered mice and rats are increasingly used as models for exploring disease progression and mechanisms. The full spectrum of anatomic, biochemical, and functional changes that develop in novel, genetically engineered mouse and rat lines must be cataloged before predictions regarding the significance of the mutation may be extrapolated to diseases in other vertebrate species, including humans. A growing list of reference materials, including books, journal articles, and websites, has been produced in the last 2 decades to assist researchers in phenotyping newly engineered rodent lines. This compilation provides an extensive register of materials related to the pathology component of rodent phenotypic analysis. In this article, the authors annotate the resources they use most often, to allow for quick determination of their relevance to research projects.     

Pathology methods for the evaluation of embryonic and perinatal developmental defects and lethality in genetically engineered mice

The normal embryonic development of organs and other tissues in mice and all species is preprogrammed by genes. Inactivation of a gene involved in any stage of normal embryonic development can have severe consequences leading to embryonic or postnatal developmental defects and lethality. Pathology methods are reviewed for evaluating normal and abnormal placenta and embryo, especially after E12.5. These methods include pathology protocols for necropsy and histopathology in addition to references that will provide additional knowledge for embryo assessment including histology atlases and advanced embryo imaging techniques.     

Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene

Objective-To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies. Animals-14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. Procedures-Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. Results-After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. Conclusions and Clinical Relevance-The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.