Vaccines of the Present and Future

Alice Wolf United States

The objective of vaccination should be to prevent or limit infection and disease caused by clinically significant infectious agents. The operative words here are clinically significant. Immunity is provided through the activities of both the humoral (antibody) and cell-mediated branches of the immune system. In addition, some veterinarians use the recommendation for vaccinations as a way to ensure client visits for yearly examinations and, least appropriate, as a �profit center.� Vaccination should be first and foremost a carefully considered and well thought out medical procedure.

A number of factors influence the host response to vaccine antigens. First is the nature of the vaccine. Generally, modified live viral vaccines (MLV) stimulate a better response than killed virus (usually adjuvanted) vaccines. Bacterins generally stimulate a less active response and less durable immunity. The route of inoculation of the vaccine, whether parenteral (IM or SQ) or local (intranasal) will also influence the magnitude and nature of the host response. The age of the patient and the presence of maternal antibodies in pediatric patients is also important. Other influential factors include nutritional and general health status, the presence of concurrent infections (e.g., parasites), concurrent drug therapy (e.g., corticosteroids), and probably some genetic factors.

Maternal antibody is a very important aspect of pediatric protection and interferes with active immune response to vaccination. Actively produced antibody (in the adult immune host) acts the same way to block response to �booster� vaccination. The amount of maternal antibody acquired by the puppy or kitten is dependent upon the immune status of the dam (particularly humoral antibody level). Once passed to the offspring, the maternal antibody will degrade at a constant rate, decreasing by about 50% every 14 days.

Types of live vaccines include virulent, attenuated, and newer viral or bacterial vectored, and plasmid DNA vaccines. Virulent vaccines are not available for small animals. These vaccines are given by an unnatural route or at an age where the animal was safe from symptoms of disease. The vast majority of small animal biologicals are attenuated products where the infectious organism has been changed to an avirulent form by egg passage, cell culture passage, or genetic manipulation (cold-adapted, deletion mutants, etc). Viral or bacterial vectored vaccines are becoming more available. They have the advantage of selectively attaching the small portion of the virulent agent that produces durable immunity to a harmless virus or bacteria that will then multiply in the host without causing disease yet producing a durable immune response to the vectored proteins. Stimulating immunity with plasmid or DNA vaccines is more selective still. Only the specific protective antigenic proteins are used in these vaccines. There is no whole living, replicating, organism involved, only some free DNA. Immune responses to this type of antigen delivery have been less active than with other delivery systems. However, there is much more work ongoing in this area and undoubtedly these selective and specific vaccines will be available in the foreseeable future. Types of killed vaccines include whole killed or inactivated infectious agents. These organisms have been killed by chemical or physical inactivation techniques. Protein subunit vaccines have also been developed that use only a portion of the infectious agent. Other killed vaccine types include cloned and synthetic peptide vaccines.

General concepts

�MLV vaccines generally produce longer duration, more solid immunity. Both humoral and cell-mediated immune systems participate strongly in the response. A single vaccination may provide significant immunologic memory (as long as there is no maternal AB interference). MLV vaccines do not, or only infrequently, require revaccination and they rarely cause hypersensitivity. It is possible for MLV vaccines to revert to virulence; however, this is an exceedingly rare occurrence. Alternatively, killed vaccines generally provide less durable and solid immunity. They require more frequent revaccination, and multiple vaccinations are needed to establish immunity and immunologic memory. Killed vaccines may require more frequent �booster� vaccinations to maintain a good level of immunity. Killed vaccines cannot revert to virulence.

The recommendation for annual revaccination is a practice that was �officially� started in 1978. This recommendation was made without any scientific validation of the need to booster immunity so frequently. In fact, the presence of good humoral antibody levels blocks the anamnestic response to vaccine boosters just as maternal antibody blocks the response in some young animals. The most reactive vaccines for dogs include leptospirosis bacterin and Borrelia vaccine. For cats, Chlamydia bacterin, FeLV and rabies, intranasal herpes and calicivirus vaccine, and Microsporum vaccine are the most common vaccines associated with adverse reactions. Vaccination reactions can generally be divided into two groups, local and systemic. Local reactions include pain at the time of injection or following, and nodule formation at the injection site. Systemic reactions may be mild (many cats have a low grade fever and malaise for 24 hours post vaccination) to severe, such as a generalized urticaria or an anaphylactic reaction. Serious concerns have been raised recently regarding the connection between recent vaccination and the development of signs of AIHA and other immune-mediated diseases in dogs. There is a clear and serious connection between FeLV and rabies vaccines and the development of vaccination-site sarcoma in cats.

Vaccine-associated sarcoma in cats has a reported incidence of between 1:1000 and 1:10,000 vaccinations depending on which report you read. The vaccines involved have been primarily FeLV and rabies vaccines although this problem has also been reported with killed (but not MLV) FVRCP vaccine. It appears to be the adjuvant accompanying the vaccine rather than the antigen that is the primary inducer of sarcoma development in these cats. Vaccine-associated sarcomas may appear months to years following vaccination. A local nodule usually appears at the vaccination site after vaccination and will precede tumor development. These tumors are highly malignant and highly invasive. They may be any of the different tumor types in the connective tissue family.

Vaccine-associated sarcomas will develop regardless of whether vaccine is given SQ or IM. Tumors are probably easier to find from SQ administered vaccines. These masses are slow to metastasize but are highly locally invasive. What you see above the surface is only the tip of the iceberg. It is nearly impossible to completely remove these tumors surgically. If attempted without appropriate pre-surgical evaluation and post-surgical radiation therapy, the tumor will become more malignant and aggressive with each removal. It is very important to inform your clients about the risk of sarcoma associated with vaccination. There is a lot of information in the lay press and on the Internet about this problem and our clients ARE often aware of it. Here is the URL of a very informative website, set up BY A PET OWNER, who had a cat die of VSA. (See www.catshots.com)

Based on a number of recent studies about management of these tumors our current recommendations are as follows:

1. Use the minimum number of vaccines truly required by each individual patient.

2. Use the least reactive products available. This means MLV products or non-adjuvanted products.

3. Use the AAFP recommended sites of vaccination.

4. Use single dose vaccines as opposed to �tank� multidose vials.

5. If a lump develops in the immediate period following routine vaccination and it does not resolve in 4-6 weeks, it should be aspirated for cytologic examination. If it persists to eight weeks, it should be excised.

6. A lump at a vaccination site developing some time later should be BIOPSIED, not completely excised.

7. If the biopsy is returned as VSA, and the owner wants the best prognosis for treatment, the cat should be referred to a referral center for CT or MRI scanning and extensive first surgery.

8. Studies are still underway to determine whether orthovoltage irradiation, brachytherapy (iridium implants), and/or chemotherapy provide the best hope for cure or disease-free interval.

9. The long term prognosis for cats with VSA is guarded and depends on the size and extent of the mass at the time of initial removal, aggressiveness of surgical removal, and efficacy of follow up therapy.

So... if there is such a risk of tumor development, should we vaccinate cats at all? The answer is, of course, yes�but judiciously and only as necessary. Dr. Fred Scott�s challenge studies at Cornell University show solid, 100% protection against a virulent panleukopenia virus CHALLENGE more than 7.5 years after a single two vaccine series of pediatric killed virus vaccination. The results of challenge 7.5 years after with herpesvirus and calicivirus were 50�65% protective and similar to the results of challenge administered 12 weeks after vaccination.

A more recent study by Dr. Mike Lappin of CSU was presented at the 2000 ACVIM meeting. In this study, he evaluated cats that had been vaccinated only once or twice, 30-36 months prior to evaluation. He measured serum antibody levels against feline parvovirus (panleukopenia, FPL), feline herpesvirus (FHV1), and feline calicivirus (FCV). He then challenged the cats with infectious levels of street strain virus. Fourteen unvaccinated cats were used as controls. USDA protocols for vaccine efficacy challenge studies were followed. For FPL, only 14 of 25 vaccinated cats had antibody levels indicating protection, yet ALL were fully immune to the virus challenge. This supports the contention that measuring serum antibody levels alone does not reflect the true state of immunity because measuring only antibody ignores the contribution of the memory antibody-producing cells and cell-mediated immunity. For FCV, all vaccinated cats had antibody levels predicting protection and all were protected at challenge. For FHV1, 22 of 26 cats had antibody levels predicting protection and these were protected against challenge. Four of 26 cats developed minor clinical signs at challenge and of these, two had �protective� antibody levels and two had unprotective antibody levels. This study again shows extended duration of immunity against active virus challenge for at least three years for FPL, FCV, and FHV1.

It is helpful to evaluate vaccines by determining what should be a �core� vaccine (i.e., needed for all dogs or cats regardless of lifestyle) and what should be an optional or elective vaccine (i.e., selected for specific risk factors for an individual animal). Generally, core vaccines for cats include: panleukopenia, feline herpesvirus, feline calicivirus, and rabies. Core vaccines for dogs include: parvovirus, adenovirus (at least for pediatric patients), canine distemper, and rabies.

Non-core vaccines would include all others available. Canine coronavirus is only a disease of puppies and causes mild, self-limited diarrhea. An older study suggested that disease caused by canine parvovirus was intensified if canine coronavirus infection was also present. However, more recent experimental evidence demonstrates that if canine parvovirus infection is effectively prevented, canine coronavirus is virtually nonpathogenic. So, the bottom line is to use an effective vaccine to prevent canine parvovirus and you won�t need to worry about canine coronavirus.

One might possibly consider using canine coronavirus vaccine in a breeding kennel with confirmed canine coronavirus morbidity in puppies. Continued vaccination of adults is not recommended or necessary. We do not stock or use this vaccine in our hospital. There is much controversy regarding the use and misuse of Lyme borreliosis vaccine in human beings as well as in dogs in endemic areas of the country. These vaccines are only partially effective and may cause serious immune-mediated consequences in some dogs that are as serious or more serious than the disease itself. Ninety percent (90%) of human cases of Lyme disease occur in only 100 counties in only eight states. The distribution of canine Borrelia infection mirrors that seen in human beings.� Lyme vaccine has absolutely no medically acceptable rationale for use in dogs in non-endemic locales.

Leptospirosis bacterin containing only canicola and ictohemorrhagica serovars is the most reactive fraction of the combination canine vaccine, is not effective against leptospiral serotypes currently infecting dogs, and is therefore not recommended for routine use. There is a newer (Fort Dodge) Leptospria bacterin that contains L. pomona and L. grippotyphosa antigens. These are the serovars isolated from the vast majority of canine leptospirosis patients. If there is a specific local leptospirosis problem known to be associated with canine serotypes, one might consider using this bacterin in more mature dogs that are AT RISK of exposure to this disease. This new bacterin has the same reactivity as the older bivalent bacterin, so may be the cause of adverse reactions.

Vaccines against contagious respiratory disease complex (CCRD, kennel cough) including Bordetella and Parainfluenza antigens should be considered for use in dogs that are boarded frequently or exposed to congregations of dogs, particularly in enclosed environments (e.g., dog shows, field trials, pet stores, etc.) where sanitation or husbandry may be questionable. Intranasal CCRD products provide more rapid onset of immunity and better local immunity but may or may not provide less durable immunity than parenteral vaccines.

Feline leukemia virus vaccine should be used for cats �at risk.� These include kittens with exposure to known FeLV-infected cats, kittens exposed to cats of unknown FeLV status, and adult cats living in confined quarters with FeLV-infected cats. Cats develop excellent age-related natural resistance to FeLV with age, so vaccination of adult cats, unless they are under constant, close exposure to virus-infected cats, can probably be discontinued by two years of age. Cats of any age with no exposure to FeLV-infected cats (all indoor cats, cattery cats, etc.) do not need this vaccine. Slick advertising gimmicks to the contrary, cats will not acquire FeLV infection by sniffing each other or sneezing through a window screen.

Feline infectious peritonitis (FIP) vaccine has limited efficacy and has been shown in an experimental study conducted by Dr. Fred Scott of Cornell University to enhance susceptibility to, and virulence of, FIP following virulent virus challenge. We now know that FIP is primarily a disease that occurs because of generation of pathogenic coronavirus mutations during replication of an endemic coronavirus carried by the cat. It is usually not a disease that is spread horizontally, as such, from cat to cat. Therefore, any cat carrying any coronavirus has the potential to develop FIP. Fortunately, such mutational events are rare. Because of limited efficacy and concerns about safety, I do not personally use nor recommend this vaccine.

Microsporum canis vaccine is not a preventative agent, can cause sterile granulomas at the inoculation site, and has not been demonstrated to accelerate mycologic cure compared to systemic and topical medical treatment alone. I do not use nor recommend this vaccine.

Chlamydia is a rare cause of conjunctivitis and mild upper respiratory disease in cats. Because it is a rare disease in household pets and is the most reactive fraction of combined feline vaccine, I do not recommend it for routine use. Catteries and pet stores are the most likely environments to have problems with endemic chlamydiosis and Chlamydia bacterin might be considered for use under these conditions.

The newest entry into the feline vaccine market is Bordetella bacterin. Except for unusual circumstances where this agent might cause problems in kittens in catteries and multiple cat environments, this vaccine is a cure in search of a disease.

Many biologics manufacturers are currently working on other vaccine products for the companion animal market. When these vaccines are introduced, there will undoubtedly be a barrage of fancy advertising brochures flooding your office and sales representatives working very hard to sell you these products. I encourage you to think carefully about whether there is a real and honest need for these products. Will these new vaccines protect your patients against diseases that you diagnose frequently and that cause them significant morbidity or mortality? Or do you have to search the literature for references because you never heard of this problem before? Please carefully examine the risk/benefit ratio for your patients before jumping on the bandwagon when new products are introduced. When it comes to vaccination, we are discovering that less... may be more... and that the same old thing... may be too much.