Table of Contents
Jenner
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Vaccination is a cost-effective means of disease prevention that has already prevented millions from death and suffering caused by the many diseases that afflict humankind. Since the advent of widespread vaccinations, the incidence of many diseases such as measles, mumps, diphtheria, pertussis, poliomyelitis, and rubella has dropped significantly. One of the great triumphs for vaccines has been the eradication of smallpox during the 1970s. While during the mid-1960s some ten to fifteen million cases of smallpox occurred, today smallpox is an affliction of the past.
Even though vaccines have been helpful in the prevention of disease, there are still many diseases that have no effective vaccine against them. Fortunately, our understanding of the human immune system has increased significantly since the days of Edward Jenner's smallpox vaccine. With this increased knowledge, vaccine design can be focused on the specific areas of the immune system which would be most effective against the pathogen in question.
The goal of vaccines is to prime the recipient's immune response in order to generate memory cells, so a heightened immune response will be elicited upon exposure to the specified pathogen. It is important that the response will occur in the correct pathways and physiological regions. Many intravenous vaccines focus on bloodborne immunity, but this would be inappropriate in a vaccine against a gut parasite, or a pathogen which entered via mucus membranes. Intracellular pathogens are not effectively guarded against by vaccines which limit themselves to the humoral pathway.
The vaccine itself should produce only limited, if any, undesirable side effects. Furthermore, it should be relatively inexpensive and mass producible for population vaccinations. These two factors are as important as efficacy when regulatory bodies and pharmaceutical companies consider possible vaccines. The cost to administer a vaccine must not outweigh its benefits if it is to be mass produced for public health. It also must not endanger its recipients, either through danger of infection and adverse reaction, or by encouraging unwarranted risky behavior. Effective vaccines (e.g. TB in the U.S.) are occasionally not incorporated into public health scheme if their use would obscure the tracking of a disease by producing "false positive" results.
The major strategies in developing vaccines are:
The use of whole organism vaccination is the oldest strategy of vaccine development. Jenner's smallpox vaccine used live cowpox virus (vaccinia) to generate protective immunity. There are two classes of a whole organism vaccine -- attenuated (live) and inactivated (killed).
An attenuated whole organism vaccine uses a non-pathogenic form of the desired microorganism. Non-pathogenicity may be induced by growing the pathogen in abnormal conditions. Those mutants that are selected by the abnormal medium are usually limited in their ability to grow in the host and be pathogenic. The advantage of the attenuated vaccine is that the attenuated pathogen simulates an infection without conferring the disease. Since the microorganism is still living, it provides continual antigenic stimulation giving sufficient time for memory cell production. Also, in the case of viruses or intracellular microorganisms where cell-mediated immunity is usually desired, attenuated pathogens are capable of replicating within host cells. However, since the vaccines contain living organisms, there is a degree of unpredictability. Attenuated pathogens have the possibility of reverting to its pathogenic form, or some attenuated pathogens which are weak enough to be contained by a normal immune system, may still be pathogenic to those with compromised immune systems. Currently, genetic engineering techniques are being used to bypass these disadvantages by removing the genes that cause virulence.
Examples of attenuated vaccines include: an attenuated strain of Mycobacterium bovis called Bacillus Calmette-Guerin (BCG) for tuberculosis, the Sabin vaccine for polio, the measles vaccine, the mumps vaccine, and the rubella vaccine.
An inactivated whole organism vaccine uses pathogens which are killed and are no longer capable of replicating within the host. The pathogens are inactivated by heat or chemical means while assuring that the surface antigens are intact. Inactivated vaccines are generally safe, but are not entirely risk free. Surface endotoxins on inactivated pertussis vaccine occasionally induce DTH responses, and influenza virus has been linked to similar reactions, though this may be due more to the immunogenicity of the egg whites in which the virions are raised. Also, inactivated vaccines do not always induce protective immunity. Multiple boosters are usually necessary in order to generate continual antigen exposure, as the dead organism is incapable of sustaining itself in the host, and is quickly cleared by the immune sysytem. Furthermore, inactivated vaccines are generally capable of only inducing humoral immunity since the killed pathogen is unable to enter into host cells. This may render the vaccine essentialy useless if the usual mechanisms of infection are intracellular.
Examples of inactivated vaccines include: vaccines for cholera, pertussis, influenza, rabies, and the Salk vaccine for polio.
As we have seen, the use of an entire organism carries some risks. Many of these can be avoided if only those parts of the pathogen which are neccesary to elicit the proper immune response are used. In this way, potential toxins may be avoided, or materials which inappropriately obscure or dominate an immune response may be removed. This precision comes at a cost, however. The antigenic properties of the various potential subunits of a pathogen must be examined in detail to determine which particular combinations will produce an effective immune response within the correct pathway.
Often a response can be ellicited, but there is no guarentee that immunogenic memory will be formed in the correct manner.. One method of producing a purified antigen vaccine is to use the polysaccharide coat of the pathogen. However, polysaccharides generally induce a T cell - independent Bcell response, characterized by a lack of isotope switching and little or no memory cell production. This proves to be of very little utility in protecting against further exposure. Adding a carrier protein aides in class switching and the production of memory B cells, but also induces the "carrier effect,""carrier effect," where memory T cells specific to the carrier, but not the pathogen, are produced. Thus T cells will not respond appropriately to infection.
Examples of subunit vaccines include: Haemophilus influenza type b
The risks and financial burden of extracting subunit antigens from pathogens can be high . With the development of recombinant DNA technigues in the past few decades, other organisms can be recruited and altered to produce the desired antigens more quickly, efficently and safely. The first commercial vaccine of this type, hepatitis B, illustrates these problems and their solutions neatly. Originally the primary component of hepatitis vaccines, HBV-soluble antigen, had to be drawn and purified from a limited number of chronic human carriers of the virus. This was a costly method, and required extensive testing of the extract to prevent the presence of active, infectious viral particles. Using recombinant techniques, non-pathogenic bacteria or yeasts were altered to produce the HBV-soluble antigen for bulk harvesting,. The dangers of viral infection were eliminated, and the mass production of the vaccine brought costs down to a level where it can now be a part of the regular childhood immunization schedule.
Examples of recombinant antigen vaccines include: hepatitis B, foot-and-mouth disease
The synthetic peptide approach to vaccine development arose in response to rapid DNA cloning and sequencing technology. This made it possible to quickly obtain primary sequences and construct various peptides. It is important to consider the dynamics of humoral versus cell mediated immunity when developing a synthetic peptide vaccine. In terms of humoral responses the focus is primarily B cells. Since B cells recognize antigens in their native form vaccinologists must identify the spatially accessible epitopes of the naturally occuring antigen and sequence these key peptides. Whether humoral or cell mediated immunity is desired T cells are vital to the generation of effective memory. Synthetic peptide vaccines are particularly useful in inducing the generation of memory helper T cells . In contrast to B-cell epitopes, T-cell epitopes are linear peptides of a relatively short length of 9 to 11 amino acids which are presented within MHC molecules. However, it is not understood in detail which peptides are immunodominant T cell epitopes. Furthermore, immunodominance of T cell epitopes is associated with MHC haplotype, so certain peptides are only effective for those with certain haplotypes. Currently, computer-driven algorithms are used to predict T-cell epitopes based on data of already known epitopes for specific haplotypes.
The synthetic peptide vaccine has had an impact on three major fronts:
T cells only recognize antigens processed and presented in the context of the MHC molecule. Endogenous antigen is produced within the host cell after bacterial or viral infection and is presented on MHC class I. This processing pathway is dependent upon the infection of the host cell by the pathogen. In order to overcome the inability of inactivated whole, purified antigen, and recombinant antigen vaccines to enter cells, recombinant vector vaccines are used. DNA that encodes the major antigenic determinants are introduced into attenuated viruses or bacteria which will replicate within host cells and express the desired gene product.
The most promising recombinant vector vaccine up to date has been the vaccinia virus. This virus can be engineered to express several recombinant genes whose products are immunogenic. Both humoral and cell mediated responses can be induced by the vector. Current research investigates the use of vaccinia for immunization against such pathogens as hepatitis B virus, herpes simplex, and influenza virus. It is questionable whether the vaccinia virus is safe for immunocomprimised individuals, such as AIDS patients, so other attentuated vectors are also under investigation as possible vaccines. Such vectors include attenuated poliovirus, adenovirus, attenuated Salmonella, and BCG strain of myobacterium bovis. Salmonella is a particularly important possibility since it can induce mucosal immunity which is needed for certain infections including cholera.
| Injection of plasmid DNA directly into recipient cells has been shown to elicit a strong immune response. This method induces a prolonged expression of the DNA encoded peptides which has been shown to promote antibodies, CD8+ and CD4+ T cells that differentiate towards the Th1 response. DNA vaccines seem to be a safer alternative to immune deficient recipients who may not be able to be immunized with live viral or bacterial vaccines. Of course, when adding foreign DNA to cells one runs the risk of sensitizing the immune cells to the DNA itself. Cross reactivity with human DNA could lead to devastating autoimmunity |  |
Injection of plasmid DNA directly into recipient cells has been shown to elicit a strong immune response. This method induces a prolonged expression of the DNA encoded peptides which has been shown to promote antibodies, CD8+ and CD4+ T cells that differentiate towards the Th1 response. DNA vaccines seem to be a safer alternative to immune deficient recipients who may not be able to be immunized with live viral or bacterial vaccines. Of course, when adding foreign DNA to cells one runs the risk of sensitizing the immune cells to the DNA itself. Cross reactivity with human DNA could lead to devastating autoimmunity.