Purity, potency, safety and efficacy remain the four cornerstones that govern regulation and secure the health and well-being of animals.

Vaccination is a necessary procedure to ensure the health of pigs in most hog operations. Fortunately, there are many product selection options. But, choosing the best option is not easy and often can be confusing.

In the early 1900s, the United States government recognized the need to regulate animal vaccines in order to ensure products were pure, potent, safe and effective. These four criteria - purity, potency, safety and efficacy (PPSE) - remain the cornerstones of vaccine regulation. Producers and their veterinarians should keep these four criteria in mind when they decide which vaccines to use and how they use them.

PPSE should be the main criteria to secure the health and well-being of the animals. Of course, price, product support and other criteria should be considered too.

In the U.S., three federal agencies are responsible for regulating animal health products. Animal vaccines are regulated by the U.S. Department of Agriculture's Animal and Plant Health Inspection Service (APHIS), Center for Veterinary Biologics (CVB).

In contrast, human vaccines and human and animal pharmaceuticals are regulated by the Food and Drug Administration (FDA).

Chemicals that are applied topically for control of external parasites are regulated by the Environmental Protection Agency (EPA).

Evolution of Rules Regulation of animal vaccines was initiated by the 1913 Virus, Serum and Toxin Act (VSTA) under this basic premise: "It shall be unlawful for any person, firm or corporation to prepare, sell, barter or exchange...any worthless, contaminated, dangerous or harmful virus, serum, toxin or analogous product intended for use in the treatment of domestic animals..." The regulations are published in Title 9 of the Code of Federal Regulations (9 CFR). This information is available at the Web site www.access.gpo.gov/nara/cfr/waisidx_00/9cfr113_00.html, or through CVB's Web site www.aphis.usda.gov/vs/cvb/).

The various sections are intertwined to avoid redundancy so a particular section, for example the section on autogenous vaccines (113.113), will refer to other sections of the code.

As expected, the regulations have changed over time as new diseases have emerged and vaccine advancements have been made.

Duration of immunity (DOI) studies are now required for licensure. Europe has had DOI requirements for years.

My own experiences in conducting licensure studies for companies tells me that the review and approval process has become considerably more rigorous in the past 20 years.

Licensing Categories Vaccines can be licensed in three categories: fully approved, conditional licensure and autogenous.

To gain full approval, the vaccine manufacturer must prove the product is pure, potent, safe and effective.

Conditional licensure is granted when the requirements of purity, potency and safety are fully met and there is a "reasonable expectation of efficacy." In most cases, conditional licenses are granted if there is an emerging disease for which no fully approved product is available.

According to regulations, autogenous vaccines or biologicals are "intended for use in isolated cases of disease of animals when licensed (federally) products are not available, or such products are unable to protect the vaccinated animals. Autogenous products can also be used to respond to emergency outbreaks of disease of animals when the immediate need for the product is such that it precludes the usual route of vaccine development."

Simply stated, autogenous vaccines can be used when licensed vaccines are ineffective or not available, or in emergency situations. Their use is not justified if an effective licensed product is available or for reasons related to product price or convenience of use.

In most situations, the use of autogenous vaccines is indicated when the strain of the microorganism in the vaccine differs from the strain in the herd and the difference results in vaccine failure.

For example, with Actinobacillus pleuropneumonia bacterins, the serotype of the strain used for making the vaccine must at least match the serotype in the herd.

In some cases, autogenous vaccines are the only rational option. In the end, producers and their veterinarians will judge if the strains are matched by how well the vaccine works in their herds.

Four Vaccine Attributes The four PPSE attributes of vaccines can be explained as follows:

Purity relates to quality and pureness of the vaccine's components and ingredients.

Potency is a quality control issue in the manufacture of the vaccine. With modified-live-virus (MLV) vaccines, potency refers to the number of live organisms in the vaccine. With killed vaccines, the amount of antigenic material is measured. Exceeding the lower threshold ensures efficacy. Staying below the upper threshold ensures safety.

With most vaccines, potency is measured by laboratory assays. For licensed vaccines, the potency of each batch is confirmed before the release for sale.

Another issue related to potency is stability. With licensed products, extensive testing is done to determine product stability, which is, in turn, used to establish the expiration date for each batch.

Safety criteria includes vaccine shedding after vaccination with MLV products, side effects such as abortion, death or severe illness and injection site lesions. MLV vaccines are tested for shedding, spread from animal to animal, and reversion to virulence by back-passing the organism through the host species several times.

For the producer, safety can be a moving target. With certain vaccines that are more likely to cause post-vaccination reactions, I prefer to safety test each new lot of vaccine by injecting a small number of pigs (25 or so), then carefully monitoring them for 48 hours. Experience tells me that safety varies by vaccine batch and farm. Some farms are more prone to post-vaccination reactions and injection site problems, even though the staff is careful in administering the vaccine and managing the pigs.

Unlike FDA's oversight of pharmaceuticals, there is no formal reporting system of adverse reactions or inadequate efficacy for animal vaccines. Consequently, the response to problems is slow and often inadequate.

Although purity, safety and potency are important, the producer's main interest is efficacy. Will the vaccine prevent disease? Will the level of prevention be sufficient to pay for the vaccine and administration costs?

For vaccines, experimental studies are required for efficacy testing. For pharmaceuticals, most are now approved through a combination of efficacy studies done under experimental conditions and in the field using naturally occurring outbreaks.

Unfortunately, efficacy under experimental conditions does not always relate well to efficacy under field conditions. However, vaccination failure is usually due to factors specific to the herd and not because the vaccine is ineffective.

There are several differences between experimental conditions and field conditions. One is the level of passive immunity at the time of vaccination (none with experimental studies, unknown or not controlled with field studies). Others include concurrent diseases (none with experimental studies, unknown under field conditions), overall care, sanitation, pig comfort and air quality (high with experimental studies, variable under field conditions), and challenge procedure (often severe with experimental studies, variable under field conditions).

In particular, challenge models poorly mimic natural infection.

Experimental efficacy studies are expensive and require great attention to detail. Developing reproducible challenge models is the most difficult aspect. A major criticism is the low number of animals used. The minimum requirement for most efficacy studies is 20 vaccinated and five non-vaccinated pigs for the initial approval, and five vaccinates and five controls for re-testing every three years.

Several preliminary studies, such as minimal vaccine dose finding studies, are done before the final or pivotal efficacy study is performed, so vaccine performance is well documented.

In the past, efficacy was based on challenging the pigs 2-4 weeks after the final vaccination. In the field, pigs are challenged for a much longer time after vaccination. Recently, CVB began requiring vaccine manufacturers to demonstrate duration of immunity (DOI), typically at least four months post vaccination.

Another issue related to vaccine efficacy is interference. This refers to the effect that one vaccine has on another vaccine administered at the same time. If antigens are combined into a single product, the company is required to perform safety and efficacy tests that clearly show that the efficacy of either antigen is not harmed by the presence of the other antigen. Conversely, interference data is rarely available when two different products are given, separately, to pigs at the same time.

In total, the vaccine manufacturer makes a claim, which appears on the label, for the relative degree of protection afforded by the vaccine. The claim usually reads: "aids in the prevention and control of losses associated with..." Claims for preventing infection are rarely granted and even claims for disease prevention are uncommon.

As with safety, producers and their veterinarians need to evaluate vaccine efficacy. The advent of all-in, all-out production has improved our ability to gather this meaningful production and health data. Slaughter examinations can be useful for monitoring vaccine efficacy for diseases such as atrophic rhinitis and Mycoplasmal pneumonia.

Testing Hurdle A major hurdle with autogenous vaccines is the need to re-isolate the organism to avoid the testing that is required with extensive use. In my experience, if the vaccine is working, it becomes difficult to re-isolate the organism. The testing required for extended use is costly and is rarely pursued.

Autogenous vaccine manufacturers are licensed by APHIS and their facilities are routinely inspected. The general protocols that are used to produce autogenous vaccines are well documented and reviewed by the inspectors. Requirements for extended use of autogenous vaccines are not considered.

Adjuvants For nearly all killed vaccines and some modified-live vaccines, adjuvants are used to augment the immune response to the antigens in the vaccine. In fact, the adjuvant can be a major determinant of vaccine efficacy and can substantially impact vaccine safety.

With both licensed and autogenous vaccines, adjuvants are approved by FDA. In my experience, this approval is primarily based on the absence of injection site lesions at slaughter, whereas, safety related to side effects and efficacy are considered in the overall approval of the vaccine.

What Is A Herd? One of the most controversial areas in regards to autogenous vaccines is the definition of herd. It is defined in the code (section 101.2) as: "Any group of animals...maintained at a common location...for any purpose. The herd includes all animals subsequently housed at the common location. If the principle animals of a group are moved to a different location, the group is still considered the same herd."

This definition was fairly straightforward when most hog farms were single-site operations. This definition is less instructive today where many operations utilize multiple sites.

Arguably, the code's definition of herd implies that an autogenous vaccine can be used as pigs move downstream through a system, but not upstream or across pig flows.

Following are excerpts from the official rules for use of autogenous vaccines as prescribed in the 9 Code of Federal Regulations (CFR), Section 113.113.

"Autogenous biologics shall be prepared from cultures of microorganisms which have been inactivated and are nontoxic.

"Such products shall be prepared only for use by or under the direction of a veterinarian, under a veterinarian-client-patient relationship."

Autogenous biologics must meet these specific requirements for use:

a. "Seed requirements. The microorganisms used as seed to prepare autogenous biologics shall be microorganisms which are isolated from sick or dead animals in the herd of origin, and which there is reason to believe are the causative agent(s) of the current disease affecting such animals.

1. More than one microorganism isolated from the same herd may be used as seed.

Under normal circumstances, microorganisms from one herd shall not be used to prepare an autogenous biologic for another herd. The administrator, however, may authorize preparation of an autogenous biologic for use in herds adjacent to the herd of origin, when adjacent herds are considered to be at risk. The following must be submitted to the administrator:

i. Name, address, and phone number of the owner of the herd of origin.

ii. Attending veterinarian's name, address, and phone number.

iii. Animal species and number in herd of origin.

iv. Identification of microorganism(s), at least to genus.

v. Diagnosis or clinical signs of the disease observed.

vi. Name and address of the person who isolated the microorganism(s) and the date of isolation.

vii. Number of doses of autogenous biologic requested and vaccination schedule.

viii. Each adjacent herd owner's name, address and phone number.

ix. Number of animals and species in each adjacent herd.

x. The attending veterinarian's or approved specialist's assessment of the involvement of the adjacent herd(s) with the disease observed.

The applicant shall give notice to the state veterinarian or other appropriate state official in writing when an autogenous biologic is to be used in adjacent herds.

The administrator may authorize preparation of an autogenous biologic for use in herds which are not adjacent to the herd of origin, but which he or she considers to be at risk of infection with the same microorganism(s).

4. Under normal circumstances, microorganism(s) used for the production of autogenous biologics may not be older than 15 months from the date of isolation, or 12 months from the date of harvest of the first serial of product produced from the microorganism(s), whichever comes first. The administrator, however, may authorize production of additional serials from microorganism(s) older than the above stated time periods, provided that the person requesting such authorization submits the following supporting information:

i. The attending veterinarian's or approved specialist's current assessment of the continued involvement of a herd with the originally isolated microorganism(s), including a summary of the diagnostic work done to support this assessment.

ii. Evidence of satisfactory protection from the previous use of the autogenous biologic produced from the microorganisms involved.

iii. Any other information the administrator may require in order to determine the need to use the microorganism to make additional serials.

b. Restrictions. Unless otherwise authorized by the administrator, each serial of an autogenous biologic shall be subject to these restrictions:

1. Microorganisms used to prepare autogenous biologics shall not be maintained in the licensed establishment beyond the time authorized for production.

2. The expiration date of the autogenous biologic shall not exceed 18 months from the date of harvest.

Testing requirements for autogenous biologics:

1. Final container samples of completed product from the first serial or subserial of an autogenous biologic produced from an isolate shall be tested for purity except that:

i. When the number of final containers in a serial or subserial is 50 or less, two final container samples from each serial and subserial shall be tested.

ii. Serials which are satisfactory after the third day of observation of purity test cultures and of safety test animals may be released for shipment to the customer and tests continued throughout the required period.

iii. Serials released on the basis of satisfactory results of third-day observations shall be immediately recalled if evidence of contamination occurs in test cultures or if any of the test animals used to demonstrate product safety sicken or die during observation.

iv. Summaries of test results shall be submitted to APHIS within four days after completion of required testing.

2. Each serial or subserial of autogenous bacterial product other than the first serial or subserial produced from an isolate shall meet the general requirements. A serial or subserial found unsatisfactory by any prescribed test shall not be released.

i. Purity test. Final container samples of completed product from each serial and subserial shall be tested for viable bacteria and fungi.

ii. Safety test. Bulk of final container samples of completed product from each serial shall be tested for safety.

iii. Identification. All microorganisms used for the production of autogenous biologics shall be identified as follows: bacteria, fungi, and mycoplasma shall be identified at least to genus and species. Viruses shall be identified at least to family. After 15 months from the date of isolation, or 12 months from the harvest date of the first serial of autogenous product produced from a microorganism, which ever comes first, characterization and identification shall be completed to strain and/or serotype before such microorganism may be used.

iv. Antigenicity or immunogenicity and potency. Persons seeking authorization to prepare additional serials of autogenous biologics from microorganisms that are older than 24 months from the date of isolation, shall be required to conduct the following tests:

A. Completed product shall be tested for antigenicity or immunogenicity in the species for which the product is recommended or in another animal species whose immunological response has been shown in the scientific literature to correlate with the response of the species for which the product is recommended. Such tests shall be conducted in accordance with a protocol developed by the licensee and approved by the administrator and the results submitted to.

B. Bulk or final container samples of completed product from each serial of such autogenous biologics containing fractions for which standard requirement potency test procedures have been established shall be tested for potency using applicable standard requirement potency tests.

If no standard requirement potency test procedures have been established for a fraction(s) in the autogenous biologic, such fraction(s) of each serial of product shall be tested for potency using a developmental potency test."