Proposed changes in vaccination protocols for companion animals, the safety of licensed vaccines and advances in vaccine technology are among the most important issues practicing veterinarians face as we enter the 21^st Century. While many would argue that these are already issues, the future promises to be especially challenging as the vaccines we use and the protocols we recommend undergo unprecedented change.

In 1998, the American Association of Feline Practitioners (AAFP) published the first report of an Advisory Panel on Feline Vaccines recommending adult cats be vaccinated every 3 years, rather than annually, against feline parvovirus (panleukopenia)...that's all...just panleukopenia. Reaction to this report was profound. Veterinarians throughout North America voiced strong concerns that anything other than annual vaccination of adult cats against panleukopenia was inappropriate, irrational, and quite possibly detrimental to the health of the cat population. Two years later, in December of 2000, the same Advisory Panel published a second iteration of the Guidelines for Feline Vaccination. In that report, the Panel expanded the "every 3 year" booster recommendation to include feline herpesvirus-1 and feline calicivirus, as well as panleukopenia. [1, 2] THEN...in February 2003, the American Animal Hospital Association (AAHA) Canine Vaccine Task Force released its Guidelines on canine vaccination.[3] In that document, 3-year booster intervals in adult dogs are recommended for distemper, parvovirus, adenovirus-2 and parainfluenza virus...indeed, change is taking place in veterinary medicine!

It is important to note, however, that the strategic issues surrounding vaccination protocols are by no means limited to whether or not a particular vaccine should be administered at 1-year intervals or 3-year intervals. In fact, there are many other compelling reasons why companion animal practitioners should review how vaccine protocols are assigned to individual patients. For example, what is the realistic risk of exposure considering a pet's environment or its age? What criteria should be used when deciding whether or not to incorporate a newly licensed vaccine into the practice? What is the difference between recombinant (genetically engineered) vaccines and killed or modified-live vaccines? Is it reasonable to perform (and charge for) serology (antibody testing) in lieu of annual vaccination? Does the practice, in fact, have a unified vaccination policy? A comprehensive review addressing these issues and controversies was published in 2001. [4]

All this considered...the question remains: are we vaccinating individual patients too often with too many vaccines? Most authors would agree that the answer to this question is "yes". The reader is reminded, however, despite all the controversy, there are many strategic issues behind these public proclamations of over-vaccination that justify the need to challenge vaccination paradigms we've lived with for the past 50 years. The discussion that follows addresses the facts and the controversies surrounding the 3 principle issues of concern to the profession today: the vaccination protocol, vaccine safety, and changes in vaccine technology. These issues will take on even more importance in the future as new vaccines continue to be introduced and as more veterinarians question the need for and safety of these products.

THE VACCINATION PROTOCOL

In 1989 the AVMA Council on Biologic and Therapeutic Agents published immunization guidelines for dogs and cats.[5] In that report, booster vaccinations for all canine and feline vaccines were recommended annually (NOTE: vaccines for canine Lyme borreliosis, canine coronavirus, canine giardiasis, feline infectious peritonitis, feline Bordetella bronchiseptica, feline giardiasis, and feline immunodeficiency virus were not available at the time these recommendations were made)^a. As recently as 1996, a survey of vaccination practices conducted in veterinary schools throughout North American indicated that annual revaccination of adult dogs and cats were routinely performed. [6] It is reasonable to assume, therefore, that most practitioners recommend annual booster vaccinations to their companion animal clientele.

However, several recent publications [1, 3, 4, 7, 8, 9, 10, 11, 12, 13] suggest that conventional practice standards for administering vaccines to dogs and cats fail to address the realistic duration of immunity (DOI). At issue is the fact that a protective immune response is likely to persist for several years following vaccination and, for selected vaccines, routine administration of annual boosters is not necessary. Despite the paucity of published DOI studies, a growing body of data supports recommendations for booster vaccination that include administering so-called "core vaccines" (e.g., feline panleukopenia, herpesvirus-1, calicivirus, canine distemper, canine parvovirus, canine adenovirus-2, and rabies) at 3 year, and longer, intervals in adult dogs and cats. On the other hand, some licensed vaccines (e.g., Bordetella bronchiseptica, leptospirosis, feline chlamydia) may not consistently provide a 1-year duration of immunity, despite a product label (package insert) that stipulates "annual booster recommended". [8]

Companion animal vaccination guidelines are currently undergoing critical scrutiny by representatives from private practice, industry, and academia. Despite widespread recommendations for annual revaccination, information available today suggests that current vaccination practices in North America do not necessarily correspond with the body of knowledge pertaining to duration of immunity derived from licensed vaccines. Companion animal practitioners should not be surprised when changes in traditional vaccination recommendations are published.

Selection of Antigens. Not only is it perceived that veterinarians are vaccinating too often, it has been suggested that pets are inoculated with vaccines containing an excessive combination of antigens. There is no immunologic evidence to support the hypothesis immune system of dogs and cats is being "overwhelmed" by the frequent administration of various vaccines. In fact, the real issue at hand for the future is to determine which vaccines are, in fact, indicated and which are not. Surveys of companion animal practitioners and veterinary teaching hospitals on vaccination protocols indicate there is considerable diversity within the profession on which vaccines should and should not be administered.

Canine and Feline Vaccination Guidelines center on what has been termed CORE and NON-CORE vaccines. CORE vaccines are those recommended for administration to every dog/cat presented to the practice. Recommendations for designating a particular vaccine as CORE are determined by: 1) severity of disease caused by the agent, 2) the risk of transmissibility the agent to susceptible animals, and 3) the potential for a particular infection to be zoonotic. NON-CORE vaccines, on the other hand, are vaccines recommended to clientele when a known or likely risk of exposure is anticipated or when the individual animal's lifestyle represents a reasonable risk of infection. Examples include feline leukemia virus (FeLV) and canine Lyme borreliosis (Borrelia burgdorferi) vaccine. It is important to understand that Vaccination Guidelines merely suggest, they do not mandate, which vaccines should be CORE or NON-CORE. However, it would seem in the interest of the individual practice to establish which vaccines meet the definition of CORE, then make the effort to assure this is communicated to all professional, as well as non-professional, staff in the practice.

VACCINE SAFETY

Among the most important issues facing practitioners today is that of vaccine safety. For most vaccines on the market today, it must still be assumed that the benefits of vaccination, when performed in accordance with currently published recommendations far outweigh the risk of vaccine-induced illness or disease. However, recent reports have raised concerns within the profession over the relationship between vaccination and delayed adverse events, specifically vaccine-associated fibrosarcoma in cats. [REFs: 14, 15] and immune-mediated disease in dogs. [16,17] Determining which vaccines pose a risk to which animals, and when, simply cannot be determined with the information available today.

Feline Vaccine-Associated Sarcoma. It is fact...administration of vaccine will induce, in some cats, tumorigenesis. In fact, the cause-and-effect relationship between vaccination and fibrosarcoma in cats has been established for over a decade.[15] And today, vaccine-associated sarcoma remains the top safety issue of concern for veterinarians and cat owners alike! These tumors are known to be aggressive, to have a high rate of recurrence, and metastasize. Although the etiopathogenesis is not completely understood, there is compelling evidence to support a relationship between post-vaccination inflammation (oxidative injury to fibrocytes and myofibrocytes) and tumor formation.

The true incidence of vaccine-associated sarcoma, which ranges somewhere between 1 in 10,000 and 1 in 1,000 cats vaccinated, is still not known. Clearly, not all cats share equal susceptibility for tumor formation following vaccination. Induction of tumorigenesis in cats is well known to be associated with extrinsic factors such as trauma, suture material, and the injection of repositol preparations, in addition to vaccine. However, much of the recent attention given to vaccine-associated fibrosarcoma in cats centers on the role of adjuvant, and adjuvant-induced inflammation.[18, 19] A recently published survey [20] identified a 5-fold increase in the occurrence of vaccine-associated sarcoma in cats receiving adjuvanted vaccine compared to cats that only received non-adjuvanted vaccine during the same 5-year period^b. Administering only non-adjuvanted vaccines to cats is not likely to completely eliminate the risk of injection-site sarcoma. However, the reduction in tumor risk associated with administering adjuvant-free vaccine to cats may ultimately prove to be significant. Any veterinarian who administers vaccines to cats has a responsibility to at least consider the option to avoid using adjuvanted vaccines in cats.^c

Adjuvant. Of particular concern is the role that adjuvant, such as aluminum hydroxide, a common component of killed vaccines used in humans and animals, has in causing the inflammatory response that, in some cats, culminates in metaplasia of fibrocytes and tumor formation. An adjuvant is, quite simply, a chemical added to killed viral and bacterial vaccines as a means of enhancing^d the immune response to a relatively weak immunizing antigen...i.e., the killed virus or bacteria. Currently, companion animal vaccine labels do not specify whether the vaccine is adjuvanted or not. Note: Vaccines that do NOT contain adjuvant include: modified-live virus vaccines, avirulent-live bacterial vaccines [e.g., intranasal administration], and recombinant vaccines.

There are several types of adjuvants used in both human and veterinary vaccines, the most common being aluminum hydroxide, aluminum phosphate, or calcium phosphate.[21] Chemically, adjuvants are a highly heterogenous group of compounds having only one thing in common: their ability to enhance the immune response. The chemical nature and the mode of action of adjuvants are highly variable; even today, it is not entirely known how adjuvant enhances the immune response to vaccine antigen. Yet, it is the adjuvant that frequently is implicated as the cause of adverse reactions, both local (injection-site) and systemic. Adjuvant-associated side effects may be ascribed to an unintentional stimulation of different immune mechanisms or they may reflect a direct, albeit transient, pharmacological effect.

Veterinarians are encouraged to follow the research reports and recommendations of the AVMA's Feline Vaccine-Associated Sarcoma Task Force when developing vaccination recommendations for cats. However, until a definitive statement can be made about the adjuvant-inflammation-tumor relationship, it is this author's recommendation that veterinarians limit the selection of feline vaccines to non-adjuvanted biologicals when ever feasible.

RECOMBINANT VACCINE TECHNOLOGY

Recombinant vaccines are among the most significant advances represented in the rapidly emerging biotechnology market. Perhaps the most significant advancement behind the development of recombinant vaccine is the ability to isolate and splice (or recombine) gene-size fragments of DNA from one organism and transfer them to another by way of a vector virus (such as the canarypox vector) or plasmid DNA. It has already been demonstrated that the hybrid organism resulting from the in-vitro exchange of genetic material has tremendous potential to deliver safe and immunogenic DNA into the host animal and, as such, represents a truly new generation of vaccine in both human and veterinary medicine. The most significant advantage of using a recombinant vaccine over conventional killed or modified live vaccine is safety. While efficacy, safety, and duration of immunity still must be established for each new vaccine, recombinant vaccines offer excellent immunogenicity in the absence of whole, killed or modified-live organisms. Furthermore, the absence of adjuvant, characteristic of recombinant vaccines used in veterinary medicine, may be an important issue in mitigating the risk of individual cats to vaccine-associated sarcoma formation.

In companion animal medicine today, 3 categories of recombinant vaccines have been recognized by the US Department of Agriculture: 1) Type 1-Subunit vaccine; 2) Type 2-Gene-Deleted vaccine; 3) Type 3-Virus Vectored vaccine. Currently, there are no gene-deleted vaccines licensed for use in dogs or cats. There is, however, one recombinant subunit OspA Lyme borreliosis vaccine approved for use in dogs (rLyme Recombitek®: MERIAL). In addition, recombinant canarypox-vectored vaccines for canine distemper (Recombitek® Distemper: MERIAL) and feline rabies (Purevax® Rabies: MERIAL). A recombinant Feline Leukemia (FeLV) vaccine is currently licensed and in widespread use throughout Europe. In the US, veterinarians can expect to see additional recombinant vaccines produced by other manufacturers in the future. The introduction of recombinant (non-adjuvanted) vaccines in the US for prevention of infections such as FeLV, FIV, and leptospirosis (multiple serovars), various tick-borne infections (in addition to Lyme borreliosis), and intestinal parasites would clearly represent and important step forward in companion animal immunoprophylaxis.

The technology behind recombinant vaccines represents the future. The practice of administering attenuated, live agents, or whole killed products is changing rapidly as immunization of dogs and cats moves from the level of inoculating whole organisms to inducing a highly targeted immune response through genetic encoding of defined antigens. [22, 23, 24]

As we enter the 21^st Century, it is anticipated that even newer technologies will be introduced giving rise to veterinary-label vaccines that are safer, have exceptional efficacy, and a duration of immunity that will potentially persist for several years, if not for the life of the patient. Veterinarians are encouraged to become familiar with recombinant vaccines, to understand the basic technology behind their development, and to become familiar with the potential advantages and disadvantages of each new product as it is introduced. Then, the clinician, considering both conventional and recombinant vaccines, will be able to administer the most appropriate product only as often and necessary to prevent significant disease.

Endnotes

a. Feline Microsporum canis vaccine was withdrawn from the market by the manufacturer in Spring 2003.
b. Data analysis is for the period 1995 through 1999.
c. Currently, Merial Ltd. maintains a complete line of non-adjuvanted vaccines for cats.
d. The name adjuvant comes from the Latin derivative "adjuvare", which means "to help".

References

1.  Richards J, Rodan I, Elston T, et al: 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines, Nashville, TN.

2.  Scott FW and Geissinger CM: Long-term immunity in cats vaccinated with an inactivated trivalent vaccine. Am J Vet Research. 60:652-658, 1999.

3.  Report of the American Animal Hospital Association (AAHA) Canine Vaccine Task Force: 2003 Canine Vaccine Guidelines and Recommendations. J Am Anim Hosp Assoc. 39:119-131, 2003. (the complete Report, including Supporting Literature, is available to AAHA members at www.aahanet.org).

4.  Ford RB (editor): Veterinary Clinics of North America: Small Animal Practice. WB Saunders, Philadelphia. May 2001.

5.  Canine and feline immunization guidelines. AVMA Council on Biologic and Therapeutic Agents. J Am Vet Med Assoc. 195:314-317, 1989.

6.  Mansfield PD. Vaccination of dogs and cats in veterinary teaching hospitals in North America. J Am Vet Med Assoc. 208:1242-1247, 1996.

7.  Smith CA. Are we vaccinating too much? J Am Vet Med Assoc. 207:421-425, 1995.

8.  Larson RL and Bradley JS: Immunologic principles and immunization strategy. Comp Cont Ed Pract Vet. 18:963-971, 1996.

9.  Paul MA and Wolf AM: Vaccinations: What's right? What's not? Proceedings of a Symposium held at the North American Veterinary Conference, January 1999, Orlando, FL.

10. Kruth SA and Ellis, JA. Vaccination of dogs and cats: General principles and duration of immunity. Can Vet J. 39:423-426, 1998.

11. Burr H, Coyne M, Gay C, et al: Duration of Immunity in companion animals after natural infection and vaccination. Research Report-Pfizer Animal Health. June 30, 1998.

12. Ford RB and Schultz RD: Vaccines and Vaccinations: Issues for the 21^st Century. In JD Bonagura (ed). Current Veterinary Therapy XIII. Philadelphia, WB Saunders. pp. 250-253, 2000.

13. Schultz R: Current and future canine and feline vaccination programs. Vet Med. 93:233-254, 1998.

14. Hendrick MJ, Kass PH, McGill, LD and Tizard IR: Postvaccinal sarcomas in cats. J Natl Cancer Inst. 86:341-343, 1994a.

15. Kass PH, Barnes WG, Spangler WL, Chomel BB, et al. Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc. 203:396-405, 1993.

16. Duval D and Giger U: Vaccine-associated immune-mediated hemolytic anemia in the dog. J Vet Intern Med. 10:290-295, 1996.

17. Hogenesch H, Azcona-Olivera J, Scott-Moncrieff C, et al: Vaccine-induced autoimmunity in the dog. In RD Schultz (ed): Vaccines and Diagnostics. Advances in Veterinary Medicine. 41:733-747, 1999.

18. Macy DW and Hendrick MJ: The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am Small Anim Pract. 26:103-109, 1996.

19. Veterinary Product Committee (VPC) Working Group on Feline and Canine Vaccination. Dept for Environmental, Food & Rural Affairs. Nobel House, London. 2002.

20. Kass PH, Spangler WL, Hendrick MJ, et al: Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. J Am Vet Med Assoc. 223:1283-1292, 2003.

21. Spickler AR and Roth JA: Adjuvant in veterinary vaccines: Modes of action and adverse effects. J Vet Intern Med. 17:273-281, 2003.

22. Babiuk LA, Lewis J, Van Den Hurk S, and Braun R: DNA immunization: Present and future. In RD Schultz (ed): Veterinary Vaccines and Diagnostics. Advances in Veterinary Medicine. 41:1630179, 1999.

23. Horzinek MC: Vaccination: A philosophical view. In RD Schultz (ed): Veterinary Vaccines and Diagnostics. Advances in Veterinary Medicine. 41:1-6, 1999.

24. Adams LG, Ford RB, Gershwin LJ, and Schultz RD: Recombinant vaccine technology. Veterinary Exchange. Compendium Cont Ed Pract Vet (Suppl). 19:5-16, 1997.