Successful vaccination against infectious diseases has been practiced for over 200 years. Indeed, it has been stated that vaccination is the most cost-effective method of reducing animal suffering and economic losses due to infectious diseases in animals. However, even with these successes, infectious diseases continue to be of economic significance to society in reduced productivity and animal death. The advent of genomics, proteomics, and biotechnology, combined with our understanding of pathogenesis and immune responses to various pathogens provides us with an unprecedented opportunity to develop safer and more effective vaccines for many pathogens. In addition to using vaccines to cure infectious diseases of animals, it is also possible to immunize animals against various hormones and cellular proteins to improve growth and alter reproductive efficiency. The present review will focus on the different types of genetically engineered vaccines that are presently at different stages of development, clinical trials, or licensing. These include: 1) live vaccines, 2) live chimeric vaccines, 3) live replication-defective vaccines, 4) subunit vaccines, 5) peptide vaccines in various modifications of monovalent, multivalent, or chimeric subunit vaccines delivered as individual components or incorporated into virus-like particles for improved immunogenicity, and 6) polynucleotide vaccines.
Subunit vaccines are defined as those containing one or more pure or semi-pure antigens. In order to develop subunit vaccines, it is critical to identify the individual components out of a myriad of proteins and glycoproteins of the pathogen that are involved in inducing protection. Indeed, some proteins, if included in the vaccine, may be immunosuppressive, whereas in other cases immune responses to some proteins may actually enhance disease. Thus, it is critical to identify those proteins that are important for inducing protection and eliminate the others. Combining genomics with our understanding of pathogenesis, it is possible to identify specific proteins from most pathogens that are critical in inducing the immune responses. The potential advantages of using subunits as vaccines are the increased safety, less antigenic competition, since only a few components are included in the vaccine, ability to target the vaccines to the site where immunity is required, and the ability to differentiate vaccinated animals from infected animals (marker vaccines). One of the disadvantages of subunit vaccines is that they generally require strong adjuvants and these adjuvants often induce tissue reactions. Secondly, duration of immunity is generally shorter than with live vaccines. In addition to using a whole protein as a vaccine, it is possible to identify individual epitopes within these protective proteins and develop peptide vaccines. The major disadvantage of peptide vaccines is that they often need to be linked to carriers to enhance their immunogenicity and, secondly, a pathogen can escape immune responses to a single epitope versus multiple epitope vaccines. To overcome some of these disadvantages, chimeric peptides can be made to broaden the immune response to different epitopes.
Live Genetically Engineered Vaccines
Live vaccines are generally believed to give excellent immune responses because they simulate a natural infection. However, conventional attenuation is generally unreliable, therefore, novel approaches to attenuation are being developed. Using molecular approaches, it is possible to identify specific virulence genes from a variety of different pathogens and to induce multiple mutations or even delete the entire gene in question - depending on the pathogen. By introducing these multiple mutations or deletions, it is possible to develop a safer vaccine than using conventional attenuation technologies. For example, the degree of attenuation can be controlled by deleting or mutating the appropriate gene or groups of genes. By deleting an entire gene or portion of a gene, the chances of reversion to virulence is dramatically reduced. The probability of reversion to virulence can further be reduced if two different spacially-separated genes are deleted or mutated. Based on these factors, these newly engineered vaccines should be much safer than conventionally-produced live vaccines. In addition, to being safer, these gene-deleted vaccines can also be used as 'marker vaccines'. By deleting an essential gene, one can develop replication incompetent vaccines which are extremely safe since they cannot be transmitted in the environment. A further advantage of live vaccines is that they can often be delivered via the natural route of infection (mucosal route), thus inducing not only systemic immunity, but also mucosal immunity. By developing mucosal immunity, one can prevent the initiation of infection as well as preventing disease.
It is also possible to introduce genes coding for protective antigens into viral or bacterial vectors, thereby immunize animals against both the vector and the pathogen from which the foreign gene was derived. These live vectored vaccines are being used to not only control infectious diseases of domestic animals, but of wildlife as well. This approach has resulted in a dramatic reduction in transmission of rabies from wildlife to domestic animals and humans. This would not have been possible by conventional methods.
The most recent development in vaccinology is immunization with polynucleotides. This technology has been referred to as genetic immunization or DNA immunization. The basis for this approach to immunization is that cells can take-up plasmid DNA and express the genes within the transfected cells. Thus, the animal acts as a bioreactor to produce the vaccine. This makes the vaccine relatively inexpensive to produce. Some of the advantages of polynucleotide immunization is that it is extremely safe, induces a broad range of immune responses (cellular and humoral responses), long-lived immunity, and, most importantly, can induce immune responses in the presence of maternal antibodies. Most recently, it has also been used for immunizing fetuses. Thus, animals are born immune to the pathogens and at no time in the animal's life are they susceptible to these infectious agents. Although this is one of the most attractive developments in vaccinology, there is a great need to develop better delivery systems to improve the transfection efficiency in vivo.