Developing vaccines that induce an effective immune response, override the impact of pathogens and provide protection can be quite challenging.
The purpose of vaccination is to induce protection against an infectious agent without causing significant disease.
Unfortunately, it is not always possible to simply inject the agent, either live or inactivated (killed), into the pig and obtain the desired protection. Successful pathogens have developed ways to adapt and survive in the host animal by evading or circumventing the immune system.
Mounting an Effective Immune Response Developing vaccines which induce an effective immune response, override any potential effect the pathogen may have on the immune system, and protect against clinical disease with minimal effect on the host, can be quite challenging.
Different pathogens call for different immune responses to control or prevent clinical disease. The immune system has many mechanisms to control invading organisms. The immune response we typically anticipate from a vaccine, which is easily measured, is a humoral immune response. This is the part of the immune system that produces antibodies.
The Job of Antibodies Antibodies, which are produced by B lymphocytes, often referred to as B cells, work in a number of ways depending on the pathogen, the type of antibody produced and the location of infection in the body. This type of an immune response is especially effective against pathogens that live outside cells, in the blood or tissues, and also on the surfaces of the body, including the gastrointestinal and respiratory systems and the skin.
Antibody production is an efficient method used by the immune system to control many pathogens, including bacteria, toxins, as a memory response to many viruses. It is an important mechanism used by vaccines to induce protection against disease.
A humoral immune response to a pathogen or a vaccine is typically determined by detecting and measuring the levels of antibodies in the serum. The presence or absence of antibodies in serum is frequently used to evaluate either exposure to a pathogen or evaluation of a response to a vaccine.
However, the presence or absence of serum antibodies does not always correlate to exposure to a pathogen, infection with a pathogen, or protection from clinical disease or clearance of a pathogen from the body.
In short, vaccines must produce the appropriate class of antibody in a site within the body where they will be effective. Vaccines and pathogens can induce the production of antibodies which have minimal to no effect on the clinical disease or the clearance of organisms from the host. Determination of type and location of the antibodies produced is based on testing and studies.
Cellular Immune Response Pathogens that infect and live in cells, especially viruses, usually require a different type of immune response. This immune response, called a cellular immune response, is carried out by several different populations of lymphocytes or cellular mediators of immunity. These cells are designated as T cells.
Unlike B cells, T cells do not produce antibodies. Specific types of T lymphocytes are capable of identifying infected cells within a pathogen. Upon recognition of an infected cell by a previously exposed and sensitized T cell, the cell is destroyed.
Measurement of cell-mediated immunity is difficult and not routinely performed. This type of immune response is especially important in the control of viruses. Generation of a cellular immune response is important for most modified-live-virus (MLV) vaccines and for killed vaccines developed for pathogens which replicate and survive within cells.
One Type of Vaccine Doesn't Fit All The knowledge that different pathogens require different immune responses is important to illustrate that not all vaccines should be identical. Likewise, they cannot be administered in the same way.
For example, a viral infection, such as swine influenza virus (SIV), will need a cell-mediated immune response in addition to antibodies which neutralize the virus.
In contrast, an infection with transmissible gastroenteritis (TGE) virus requires an immune response at the mucosal level of the intestinal tract. For TGE, an oral vaccine may have increased efficacy.
Combining multiple antigens (protein or carbohydrate substance capable of stimulating an immune response) and organisms within a vaccine must be done with care. The combination of some vaccines and pathogens may result in a decrease, or even loss, of efficacy of the vaccine against the pathogens.
There are a number of mechanisms by which combining either antigens or vaccines can diminish the efficacy of one or all of the antigens.
One possible mechanism is that the methodologies used to inactivate one organism may cause changes to the other antigen(s) in a manner that results in loss of protection from disease. Different protocols are used to inactivate different pathogens and care must be taken to use the appropriate techniques.
Combining killed and MLV vaccines can be problematic for that reason. The method of inactivating the killed product can also inactivate the MLV pathogen, thereby changing the mechanism by which a protective immune response is to be elicited.
In addition, the antigen of one pathogen may drive the immune response in a direction that is inappropriate for a second antigen. This is not to say that antigens can't be combined to allow vaccination for multiple pathogens. But, commercial vaccine manufacturers which combine multiple antigens must demonstrate that there is no suppression of the immune response or loss of efficacy to any of the antigens in the production of the vaccine.
An autogenous vaccine does not have to be tested in a similar manner. The result is that multiple antigens within one autogenous vaccine may or may not be efficacious. No scientific studies are performed to confirm the efficacy and lack of interference between antigens.
A good vaccine takes into account both the environment in which a particular pathogen colonizes the host, and the type of immune response required to induce an effective and protective immune response.
To induce an effective immune response, the appropriate amount of antigen must be present in the vaccine. Too much or too little antigen may bring about either the wrong immune response or no immune response at all, thus providing no protection.
The immune system is carefully balanced and, as a rule, more of either an antigen or an immune response is not necessarily better.
Commercial vaccines determine the amount of antigen used to stimulate a specific immune response using challenge studies in the host animal. Generally, the development of an antibody response alone is not sufficient to decide if the optimal amount of antigen is present within a vaccine.
For their part, autogenous companies don't have to demonstrate whether the amount of antigen in their vaccines is appropriate. The amount of antigen is usually determined by either the unit of the pathogen, such as colony-forming units, or by the level of protein in the vaccine preparation. The protein level is usually a poor measurement of the exact antigen needed to induce an effective immune response. Autogenous vaccines are not required to conduct studies in the host animal.
The Role of Adjuvants As a rule, adjuvants (oil or water-based compounds) are added to vaccines containing killed pathogens to boost the immune response. Most MLV vaccines do not contain adjuvants, although there are exceptions.
The type of adjuvant used determines the direction and type of immune system induced. Different pathogens require different adjuvants to ensure that the correct immune response is produced. Recent advances in our knowledge of the immune system are leading to the development of adjuvants which can specifically direct the immune response to a pathogen.
Testing must be performed, however, to demonstrate that the adjuvant is safe and that it does not cause adverse reactions or the formation of local reactions or abscesses.
The Goals of Vaccines For their part, commercial vaccine companies are required to conduct studies demonstrating that a vaccine and its adjuvant are safe for use in food-producing animals and do not result in damage to the host.
Killed vaccines are produced by inactivating the pathogen. This is done using a chemical, such as formaldehyde. The organisms used in killed vaccines do not infect the animal.
Current regulations require that all autogenous vaccines consist of killed and inactivated organisms. This rule is to ensure that the pathogen is not infective and therefore cannot be shed. The strategy of allowing only the use of killed organisms is intended to decrease the possibility of disease or damage by the vaccine. An autogenous vaccine manufacturer does not have to demonstrate safety in the host animal.
However, killed vaccines are not always the most efficacious in producing a protective immune response.
MLV vaccines contain live organisms but generally do not contain adjuvants. Instead, the goal of the MLV vaccine is to induce a mild, non-clinical infection in the host. Organisms are selected or produced which induce minimal to no clinical disease. The immune response generated by a MLV vaccine is similar, if not identical, to that induced by infection.
This type of vaccine is frequently used with viral pathogens and specific types of bacteria which multiply in the host animal's cells. The organism is made less pathogenic (attenuated) using a number of mechanisms. These include growing in cultured cells, using non-pathogenic strains of the organism, or with the advent of molecular biology, or altering the organism genetically so it no longer causes clinical disease.
Many attenuated organisms reproduce poorly in the host animal, which may be a mechanism for reducing disease while inducing an immune response.
Although attenuated organisms usually have a number of mutations to prevent the onset of disease, it is possible for a non-pathogenic strain to revert to virulence (capable of causing infection). This can be done either through genetic mutation or combining with other strains to make new strains.
Attenuated organisms can also pose a risk to immunocompromised animals as they may behave like virulent opportunistic organisms due to the weakened immune system.
MLV organisms can't be used in autogenous vaccines.
Protection against a number of diseases, especially viruses, is enhanced with the use of MLV vaccines. The use of autogenous vaccines under these circumstances is often impractical.
Vaccine Trials Our laboratory at Iowa State University in Ames, IA, has performed research on Mycoplasmal pneumonia, porcine reproductive and respiratory syndrome (PRRS) virus and SIV.
If we compare the immune response induced by these three common swine pathogens, and the vaccination strategies required for protection from clinical disease, we find significant differences.
Mycoplasmal Pneumonia Mycoplasma is a bacteria that infects the cilia of the respiratory tract. The presence of antibodies in the serum does not reflect the ability of a vaccine to protect against mycoplasma. The presence of antibodies in the respiratory tract appears to be important in the prevention, control and resolution of clinical disease.
Mycoplasma is an extremely difficult organism to isolate and requires special media for growth. And, it is extremely slow-growing, often taking several months to grow to a detectable level. Contamination with other bacterial or mycoplasma organisms makes the isolation of mycoplasma difficult, if not impossible.
Mycoplasma vaccines are produced from killed organisms. Use of MLV mycoplasma vaccines is not advised as injection of live organisms into pigs may result in clinical disease consisting of arthritis and polyserositis.
Commercial vaccines against mycoplasma induce the production of antibodies in the airways and lungs where the organisms colonize. These vaccines are generally efficacious against mycoplasma. Vaccine failure is usually due to other factors such as the immune status of the pig or timing of the vaccination.
The need for autogenous vaccines against mycoplasma is questionable. The current autogenous products may or may not contain pure cultures of mycoplasma and, in our experience, are frequently contaminated with other non-pathogenic mycoplasmas.
Thus, the amount of antigen in the vaccine specific for mycoplasma may be inadequate to induce protection. There is also no evidence of sufficient antigenic variability between mycoplasma isolates to justify the use of autogenous vaccines. The use of autogenous vaccines is only lawful if the commercial products are not protective or controlling the disease.
Swine Influenza Virus In contrast, SIV is a virus which infects the epithelium (thin layer of cells which covers and serves to enclose parts of the body) of the respiratory tract. The virus remains primarily in the respiratory tract.
SIV infection induces an effective immune response consisting of both antibody production and, more importantly, a cellular immune response.
Current vaccines against SIV are killed products which induce both a humoral (antibodies) and a cellular immune response. Factors such as the presence of maternal antibodies may play a role in the efficacy of a SIV vaccine.
SIV is a concern to the swine population due to the mutations which occur while the virus is replicating. SIV evades the immune system by several mechanisms. One is by undergoing constant, minor, genetic changes as it replicates. Consequently, over time, the virus changes enough to appear to be a new organism to the immune system. The lymphocytes and antibodies which previously recognized the virus and virus-infected cells are no longer effective, requiring the generation of new cells and antibodies.
A second mechanism by which SIV evades the immune system consists of recombination of larger genetic segments resulting in entirely new strains.
Historically, the hog population in the United States was infected with a SIV strain designated as H subscript 1N subscript 1, based on the genetic makeup of the virus. Recently, the emergence of H subscript 3N subscript 2 strains has occurred due to the recombination of the different genetic segments.
Vaccines are not protective against the different strains of SIV. That means vaccines produced with H subscript 1N subscript 1 virus strains are not protective against the newly emerged H subscript 3N subscript 2 strains. New vaccines have been developed to control the new strain(s) of SIV.
Proper diagnostics must be performed to confirm that SIV is present and the cause of disease. Care must be taken that the autogenous SIV vaccines contain the farm strain.
Care must also be taken that the vaccines are properly inactivated as use of live virus could potentially lead to more recombination and therefore to new strains of SIV. Efficacy trials are not performed by autogenous companies to confirm the vaccine is capable of inducing protection.
PRRS Virus Confounders In contrast to SIV, PRRS virus does not appear to induce an effective immune response, either cellular or humoral. And, PRRS virus replicates or reproduces throughout the body and does not remain in one specific area like SIV or mycoplasma. Antibodies produced following vaccination or infection are not very effective in the control of the virus.
PRRS virus evades the immune system in a number of ways, including alteration of the immune response and by constantly changing the viral genetics through mutation and recombination. The process of recombination is where different strains of the virus switch genetic material with each other, forming a completely different population of viruses.
Little is known about the effect of PRRS virus on the immune system. However, it has been determined that although PRRS infection frequently increases the production of antibodies, the antibodies produced are often not effective in eliminating the virus from the pig.
It has also been demonstrated that antibodies produced against PRRS virus can enhance virus infection and replication within macrophages. PRRS infects and destroys macrophages, which are important cells in the immune system. Macrophages engulf and destroy bacteria and foreign substances in the body. At the same time, the macrophages present small pieces of the pathogens to the immune system for recognition. This activates the immune system to destroy the pathogens.
The impact of PRRS virus on the macrophages plays an important role in the induction of increased secondary diseases.
PRRS virus is an extremely frustrating organism to work with in terms of developing effective vaccines. The requirements for an effective PRRS vaccine are not known. Whether an MLV or a killed product will induce protection still is controversial.
The efficacy of autogenous vaccines produced to control PRRS virus is unknown. Therefore, the use of autogenous PRRS virus vaccines, which are required by law to be killed, is also questionable.
The immune response necessary to protect against PRRS-induced disease is unknown. Measurement of antibodies alone is insufficient to determine the efficacy of a PRRS vaccine. The vaccine should aid in controlling the disease and not increase the duration of virus shedding or even severity of disease.
Research has shown that vaccination and infection with different isolates of PRRS virus does not induce cross protection.
The effect of PRRS virus on the immune system can be important in disease control and vaccination strategies. Recent research has demonstrated that the presence of PRRS virus can significantly decrease the efficacy of mycoplasma vaccines.
On the other hand, PRRS infection does not appear to affect use of an MLV vaccine against pseudorabies. These studies demonstrate that the interaction between the various pathogens and vaccines must be considered on an individual basis when considering disease control and intervention strategies.
Tools of Disease Control In conclusion, the immune system is extremely complex. It uses multiple mechanisms to control invading pathogens. Vaccination is an important tool in disease control. Use of quality products is important to ensure that the immune response induced by vaccination is efficacious and safe.
In order for a vaccine to be cost effective, it must be efficacious with minimal side effects. Knowledge and science should be important factors in the decision of the appropriate vaccines for disease control.