10.4 Biological Products

According to the USDA Animal and Plant Health Inspection Service CVB (USDA-APHIS-CVB), biological products refer to compounds made from living or genetically engineered organisms, including vaccines, bacterins, antitoxins, immunostimulants, or diagnostics. All veterinary biologics are used to prevent, treat, or diagnose animal diseases through an immunological method or process. All veterinary biologics are under the control of the USDA-APHIS-CVB under the 1913 Virus-Serum-Toxin Act. The CVB carries out the provisions stated in Title 9 of the CFR, parts 101–118, to ensure that biologics are effective and safe for animals and people.

As of the most current licensed products for aquatic animals list, there are eight licensed biologics for fish available in the United States.^[1] Progress has been slow in developing effective vaccines for aquatic food animals. Yet in other countries such as Norway in the Atlantic salmon industry, antibiotic use has been reduced with effective vaccines.

Vaccines

The first vaccines attempted for fish were tested around the time penicillin was discovered in 1928. There are numerous routes of administration to consider in fish (e.g., bath immersion, oral, and injectable). Not all products can be administered by all the routes. Immersion is the simplest. So-called bath vaccinating is a variation of the duration of the immersion method. Immersion is especially effective in the very early life stage when fish are too small for injection. Feed administration is another way to immunize fish through the routine of feeding. Of course, there is a chance that, with mass immunizations such as immersion and feed-administered vaccines, some individuals will miss the immunization by not eating or otherwise not getting enough antigens to develop protection. Injecting each fish is best if the fish are large enough to be injected and the vaccine will not cause harvest problems with adhesions and other rejection characteristics. The injection method is extremely labor-intensive, and a few companies have introduced automated vaccinating equipment. As a note of caution against personnel self-injecting certain fish biologics, serious reactions, including death, have been recorded. The main cause of harm is the adjuvant agent in the vaccine formulation.

Vaccines are prepared to prevent disease. The mechanism behind them is the preparation of the adaptive immune response for future encounters with pathogens. Almost any etiologic agent that the immune system can control is theoretically capable of being vaccinated against. Generally, three types of vaccines are licensed:

• live (usually modified live),
• killed, and
• subunit.

Of the vaccines in Table 10.2 listing USDA-licensed fish biologics, three are live products: Arthrobacter for salmonids, Edwardsiella ictaluri for catfish, and Flavobacterium columnare for catfish. The two modified live catfish vaccines are attenuated live preparations from less virulent strains. The modified live vaccines are attenuated in the laboratory in a variety of ways to lose their ability to cause disease. These attenuated strains are typically better at stimulating the cellular side of immunity and achieving better outcomes in preventing intracellular pathogens and longer-lasting protection. There are instances in which the attenuation does not reduce the pathogen’s virulence enough to allow some species’ immunocompromised or very young offspring to be safely vaccinated.

Currently, four of the eight USDA-licensed fish biologics are a killed product: Aeromonas salmonicida bacterin for use in salmonids in a combination product for A. salmonicida-Vibrio anguillarum-Vibrio ordalii-Vibrio salmonicida bacterin labeled for use in salmonids. There is also infectious salmon anemia virus vaccine and a Yersinia ruckeri bacterin for use in salmonids. Notice that most of these pathogens are not intracellular. Killed bacterins were the first vaccines developed using a simple method of inactivating live bacteria in formalin.^[2] In contrast to live vaccines, killed vaccines are more stable in the environment and less expensive to produce but elicit a weaker immune response unless well adjuvanted. They are also safer than attenuated vaccines. Nonetheless, there is the miniscule chance of improper killing of the pathogen during production, leading to the disease that was meant to be prevented. Killed bacterins are often challenged to produce robust, long-lived cellular immunity. This relative lack of robust immunity results in a shorter duration of protection with humoral immunity. Adjuvants and immunostimulants play a key role in more desired outcomes.

One of the eight USDA-licensed biologics is a subunit vaccine for infectious hematopoietic necrosis virus. This biologic is made of DNA from the virus that is immunogenic and protective. Subunit vaccines are composed only of parts of the pathogen to elicit an immune response in the host. These vaccines are the safest because there is no possibility of replication or infection of immunocompromised hosts. The tradeoff is that they stimulate the weakest immune response of the three vaccine types. This lack of stimulation is due to the lack of an array or diversity of antigens for the host’s immune system to recognize for future infections.

Diagnostic kits for early detection or diagnosis of animal diseases are considered biologics regulated by the USDA when these products are for a specific disease diagnosis. Table 10.2 above does not list any diagnostic kits for fish pathogens. Specific pathogen detection kits are not typically regulated in diagnostic and regulatory laboratories.