PawPeds

Feline vaccination

[Translated by Catherine Muller-Sautreau, Cattery Ailuropus.]

By Marie-Bernadette Pautet, Chacolaterie's Somalis, 2006.
Report on 2006/03 SFF seminar entitled "Update on Feline Vaccination".
(Reprinted with permission).

About 50 breeders and veterinarians attended the seminar organized by the French Felinotechnic Society (SFF), held at the national veterinary school in Maisons-Alfort on 2006, march 25^th, to review current knowledge on feline vaccination.

This article tries to sum up this seminar's highlights, in order to inform breeders who couldn't or wouldn't attend. The lecture texts, together with a reprint of their visuals, can be ordered through the SFF for 45 € (texts in French).

My notes will follow these outlines:

Immunology of vaccination
Types of vaccines and vaccination protocols
Infectious diseases prevalence
Leukemia
Towards a vaccination against FIV and FIP?
Vaccination and fibrosarcomas

Even though I have put every effort in attempting to reflect the lecturers' opinions the best I could, I welcome attendees or lecturers to share their comments on this summary, should any oversight or error be found.
The first lecture was a rather technical one, fairly out the reach of those who did not have previous knowledge about the way body's natural defenses work.

1. Immunology of vaccination

Lecture by Dr. Jennifer Richardson (Alfort Veterinary School).

Immune responses (IR) fall into two categories: innate immune responses are fast to be induced, whereas adaptive immune responses take more time. Those last, to be found in vertebrates only, are more deeply studied: only they have memory, a feature vaccination directly takes advantage of. Yet, it has been recently discovered that innate IR are required for adaptive IR to be triggered; hence both should be understood and taken into account in vaccines development.

Innate IR aren't specific to any particular pathogen. They are mediated by:

Pro-inflammatory responses through phagocytes;
Release of interferons that enhance resistance to viral infection;
Dendritic cells activation. Those cells can recognize a broad range of pathogenic agents through their TLR receptors. Actually, they recognize what are called PAMP (Pathogen-Associated Molecular Patterns). Once activated, dendritic cells trigger adaptive IR by presenting antigens to T-cells, a "red alert" for them.

Adaptive immune responses fall into:

Humoral-mediated responses: once turned into plasmocytes, B-cells can secrete antibodies (immunoglobulins).
Cell-mediated responses, where T-cells play a key role. T-cells can recognize antigens fragments specifically (once activated antigen-presenting cells have processed and bound them to major histocompatibility complex (MHC) molecules).
T-cells express either CD4 molecules (CD4+ T-cells) which recognize antigens peptides from extra-cellular origin in association with MHC class II molecules, or CD8 markers (CD8+ T-cells) that interact with antigen peptides from intra-cellular origin in association with MHC class I molecules.
Some pretty recent studies have shown that CD8+ T-cells memory responses to infections and vaccinations are CD4+ T-cells dependant. CD4+ T-cells activate B-cells as well in humoral responses. Those cells thus interact in several ways.
T helper cells (TH), another kind of T-cells, can be subdivided into two main subsets (TH1 and TH2) according to the cytokines they produce. TH1 promote cell-mediated IR, while TH2 stimulate humoral responses.

Immunological memory, upon which vaccination relies, involves long-term plasmocytes as well as memory B- and T-cells. Effective responses are way faster to set in than when the antigen was encountered for the first time.
For a vaccine to be efficient, memory IR ought to be induced quickly when the vaccine-targeted pathogenic agent challenges the body. Yet, this requires the proper innate IR to be induced as well. This aim is often achieved by adding PAMP or similar molecules as adjuvants in subunit vaccines. Depending on each particular pathogenic agent, the vaccine should also stimulate rather TH1 or TH2 effectors to direct adaptive IR toward the best pathway.

2. Types of vaccines and vaccination protocols

Lectures by Pr. Jean-Pierre Gannière (Nantes Veterinary School), Pr Oswald Jarrett (University of Glasgow) and Dr. Hervé Poulet (Merial).

It should be kept in mind that the three aims of vaccination are:

avoiding serious disease onset by preventing or reducing clinical signs (for the animal itself);
reducing both carrier state and virus spread incidence (for the group);
avoiding zoonosis transmission (for humans).

No vaccine is 100% efficient. Vaccines usually prevent both infection and disease, but in URI's case (calicivirusis and herpesvirusis). As far as these viruses are concerned, the effects of the disease are reduced, but infection cannot be avoided (due to the antigenic differences that can be found between the virus used in vaccines and those encountered in the field).

Available feline vaccines can protect against some viral diseases as well as bacterial ones.

There are several vaccines types. The "classical" ones contain the whole pathogenic agent, either live or killed, while the more recent vaccines are based on pathogenic agents' subunits, or express recombinant DNA (some of the pathogen's genes are inserted into non-pathogenic bacteria or virus). One of their advantages lies in the possibility to have the final product purified, thus avoiding risks of contamination by other biological or infectious componants.
The vaccines fall into:

modified-live agent vaccines, that is to say the agent can still be replicated but its virulence has been attenuated;
inactive agent vaccines, that is to say the agent can no longer be replicated;
subunit vaccines;
recombinant vectored vaccines.

Because of the supposed link between adjuvants and fibrosarcomas (see below, section 6), the issue of adjuvants presence has been raised in the audience. Yet, adjuvants remain a key feature to some vaccines efficiency, especially for killed and subunit ones where they're needed for the active agent to be properly presented to the immune system.

Rabies

Rabies virus belongs to the lyssavirus family. In France, all licensed vaccines are statutorily inactivated and adjuvated (either with alumin hydroxid or alumin phosphate): Enduracell® R mono (Pfizer), Nobivac® Rage (Intervet), Rabigen® Mono (Virbac), Rabisin® (Merial), Unirab® (Fort Dodge) or Quadricat® (Merial).

A recombinant vectored vaccine using canarypox virus to express a rabies virus glycoprotein (Merial Purevax® Feline Rabies) offers perspectives and may be licensed in France, were legislation amended. [Editor's note: this vaccine is licensed in other countries.]

Current vaccines do not appear to protect against another form of "rabies", a bat-transmitted lyssavirus (EBL-1 virus).

Panleukopenia or feline distemper

This is the most contagious and serious feline disease.

FPV (Feline Parvo Virus) is highly resistant. Yet this fairly stable virus has only one serotype, so currently licensed vaccines have proven to be greatly efficient. All FPV vaccines are classical ones, either using modified-live agents (in multivalent vaccines, but Merial Purevax® P) or inactivated one (adjuvated Fort Dodge Fevaxyn® Pentofel).

Feline rhinotracheitis or herpesviruses

FHV (Feline Herpes Virus) accounts for 40% of URI cases. It is also conjunctivitis and keratitis first cause. The virus can remain latent, so infected cats may exhibit frequent recurrences.

There's only one FHV serotype, whose antigenic features are stable. Typically, vaccines against herpesvirusis are classical ones, using modified-live agents in bivalent products (protection against herpesvirusis is always combined with protection against calicivirus) or even tri-, quadri- or pentavalent vaccines, but for Fort Dodge Fevaxyn® Pentofel (a killed whole-organism vaccine) and Merial Quadricat® (subunit vaccine).

Feline caliciviruses

There's only one FCV (Feline Calici Virus) serotype, but a lot of antigenic variants exist (highly-variable regions in the virus capside's proteins). Once infected, 15 to 20% of cats remain chronic carriers. Typically, FCV vaccines use modified-live agents in bivalent products (always associated with FHV, as mentioned above) or killed agents vaccines, either adjuvated (Fort Dodge Fevaxyn® Pentofel and Merial Quadricat®) or not (Merial Purevax®). All of them help reduce clinical signs but cannot prevent the infection to occur.

Hemorrhagic-like fevers caused by calicivirus, whose first outbreaks took place in the US, are now reported in Europe as well. The usual vaccines barely protect against this calicivirusis variant.

FCV have been isolated in 90% of chronic gingivostomatitis cases. It thus appears that FCV infection and immune response deregulation (unusual shift to a mixed TH1 and TH2 response) are two key factors in this still poorly understood disease.

To improve calicivirus vaccination efficiency, Merial recommends to use recent and immunodominant strains. Under vaccination pressure, antigenic mutations have occurred and resistant strains have raised. It is safer to use a recombinant or inactivated agent to avoid potential residual virulence from modified-live vaccines. The new adjuvant-free inactivated M725 vaccine combines two immunodominant strains from distant antigenicity.

Feline leukemia

FeLV (Feline Leukemia Virus) is a very labile virus. Infection by FeLV is persistent since this retrovirus can be integrated into the cell's DNA.

All currently available FeLV classical vaccines, using either killed whole-organism or subunits, are adjuvated (this feature being required for their efficiency). A non-adjuvated recombinant vaccine exists and uses an attenuated canarypox vector expressing two of the FeLV genes.

Feline chlamydophilosis (used to be called "chlamydiosis")

Its pathogenic agent is chlamydophila felis, a resistant bacteria that leads to chronic carrying. Vaccines against it are all included into multivalent products. They are based either on modified-live agents or inactivated whole-organism ones.

A vaccine against bordetella also exists (not licensed in France). An attendee shared experience of using canine vaccine with good results on kittens.

Recommended guideline

There's no justification in vaccinating each cat against every disease. Protocols should be adjusted to each particular case. Studies were conducted to assess vaccines duration of immmunity, and, today, general recommendations can be summed up as follows:

Indoors cat (without any contact with cats of unknown status):
Distemper (P) + URI (RC)
Cat who may encounter other cats of unknown status:
Distemper (P) + URI (RC) + Leukemia (FeLV)
Traveling cat:
Distemper (P) + URI (RC) + Leukemia (FeLV) + Rabies (R)
Cat living in a multiple-cat environment:
Emphasis on sanitary management;
Distemper (P) + URI (RC) + Leukemia (FeLV) + Chlamydophilosis (?)
Cat entering a multi-cat household:
Sanitary status check-up (FIV, FeLV, ...);
Quarantine;
Systematic revaccination.

Vaccination schedule

It is now widely accepted that duration of immunity persists over a year for several vaccines.

Thus, the overall guideline for vaccination intervals, apart from slight variations, is:

Primary series around 8-9 weeks, with a second dose 3-4 weeks later (not until the kittens are 3-month-old). J.P. Gannière suggests an additional shot at 16 weeks for kittens living in multi-cat environments;
First booster 12 months later for every vaccine;
Annual boosters against herpes/calici (RC) and rabies if needed (R).
O. Jarrett suggests a booster every 3 years against RC.
Annual boosters against FeLV if needed.
O. Jarrett suggests a booster every 2 years.
Boosters every 2 or 3 years against distemper (P).
J.P. Gannière suggests an annual booster.

An attendee raised the issue of sanitary controls in cat shows, for, even though acknowledged guidelines recommend a booster every 2 or 3 years only, exhibitors may dread they might be denied the right to enter the show if their cats' last shots are more than a year apart.
Most vaccines licenses specify an annual booster is needed, hence a veterinarian who chooses to revaccinate every 2 or 3 years only takes it under his responsibility (this is furthermore true when it comes to European passport, where the veterinarian has to write down the next boosters prospective date).
Sanitary controls in cat shows shouldn't ask for more than is statutorily required and Dr.Anne-Claire Chappuis-Gagnon undertook to spread the information, practitioners being moreover already aware of recommendations guidelines making annual booster uncompulsory for some vaccines.

Here are two questions to test your reaction to preconceived ideas:

With a given antibodies titer, a cat is protected against infection and disease: RIGHT or WRONG?
A given antibodies titer is compatible with the fact that the cat has been properly vaccinated and is likely to be protected against the disease: RIGHT or WRONG?

Answers at the bottom of the page^[1].

Author's note: one might consider AAFP's (American Association of Feline Practitioners) 2006 feline vaccination guideline an interesting online reading.

3. Infectious diseases prevalence

Lecture by Dr. Corine Boucraut-Baralon, Scanelis.

In Scanelis laboratory (Toulouse), the most asked for analyses look for coronaviruses (30%), caliciviruses/FCV (23%) or herpesviruses/FHV (20%) and chlamydia (10%). Screenings for FeLV and FIV are barely asked for since PCR tests are seldom used for mere preventive purpose.

An European survey on feline URI's prevalence (herpesvirus, calicivirus, chlamydophila, bordetella and so on) showed that:

hygiene plays an important role in infections frequency, especially when it comes to chlamydophilosis;
FHV and FCV co-infections are common in FHV+ catteries;
there's a correlation between the number of cats living in a household and infections frequency.

When it comes to coronaviruses and FIP, epidemiology is a complicated matter. Enteritic coronaviruses are thought to be present in 80% to 100% of European catteries. The animals environment is an important factor in the risk of developing FIP:

Age (2/3 of wet FIP cases occur in cats less than one year of age);
Cattery's size (risks increase with the number of cats housed);
Stress (overpopulation, conflicts, pregnancy/lactation, moving, new cat introduction, and so on);
Sanitary conditions;
Genetic factors and immune system shape.

Unfortunately, panleukopenia (distemper) still exists: 186 cases were registered in France between 2003 and 2005. This disease typically breaks out in multi-cat environments (shelters, associations, pet shops). It seldom occurs in catteries (3% of the cases), which can be mainly explained by systematic vaccination and good sanitary management. Young cats are particularly at risk (half of the cases happen in kittens under 3 months and 94% of all cases are cats less than one year old).

4. Leukemia

Lecture by Pr. Oswald Jarrett, University of Glasgow

Leukemia incidence has deeply decreased for the last 20 years, especially in pedigreed cats. Pr. Jarrett mentioned the instance of Abyssinians in the UK, where 35% of Abys were positive in 1980 and 0% in 2000. This can be credited to positive cats identification through testing, subsequent isolation and vaccination development.

Leukemia is almost always lethal (85% of positive cats die within 3.5 years to lymphoma, leukemia, anemia, aso). It is transmitted by saliva; close contact and mutual grooming contribute to its spreading. In a closed environment (without any new cat introduction), leukemia remains self-limitative. When a cat tests positive, all cats in the household must be tested. Positives and negatives should be separated, then they should all be retested 12 weeks later (some may have fought off to negativity, some may now have become positive), and so on until a series of stable results is obtained.

Available vaccines fall into different types (subunit, inactivated whole-organism, recombinant), but all are efficient. Studies in the UK showed that they protect 75-80% of kittens. Even if adults are far less susceptible to leukemia than kittens (a same virus dose infects 100% of kittens and 20% of adults), they have a lot to gain in being vaccinated if they can be in contact with cats whose status isn't ascertained.

Quick tests proceeded in veterinarians offices are highly sensitive (there're few false negatives) but rather less specific (some false positives might occur). If a healthy cat tests positive, the diagnosis should always be confirmed through an additional test (immunofluorescence or PCR) to rule out a false positive result (though false positives seldom occur with symptomatic cats).

5. Toward a vaccination against FIV and FIP?

Lecture by Pr. Oswald Jarrett, University of Glasgow.

FIP

Feline enteritic coronaviruses (FCoV) are oro-fecally spread. After initial exposure to the virus, 10% of cats become permanently infected, 85% are temporarily infected and 5% entirely resist the infection.

Pfizer has developed a vaccine (Primucell®). It consists of an attenuated, temperature-sensitive mutant-FCoV intranasally administered, and isn't available in many countries. Several studies were conducted to assess this vaccine's efficiency. A survey of 500 cats in a US shelter showed a 0.8% FIP incidence in vaccinated cats, whereas 3.25% of non-vaccinated cats developed the disease. A study in Switzerland showed that the vaccine wasn't efficient if the cats had been infected by FCoV prior to the vaccine's inoculation. This is an issue, for kittens are typically infected by their mother before they can be vaccinated.

FIV

Several experimental vaccines have been developed. The issue with FIV is that cats do not overcome a FIV infection, since it's persistent in lymphocytes. A "sterilizing immunity" should be obtained, which is very hard to get.

For now, the most effective level of protection is reached with inactivated whole-organism agents vaccines, such as Fort Dodge Fel-O-Vax FIV® licensed in the US.

Conversely to leukemia virus that has no variation, there're several FIV subtypes. This vaccine protects against the B subtype, but is inefficient against the A subtype. Yet, the A subtype is fairly representative of European most common strains, and it's the most virulent one as well.
A vaccinated cat has FIV antibodies, hence it cannot be distinguished from a FIV-positive cat using the common diagnosis tools. A potential FIV infection must be looked for through PCR tests.

6. Vaccination and fibrosarcomas

Lecture by Dr. Anne-Claire Chappuis-Gagnon, Lyon.

Fibrosarcomas are often described in old cats. Following the identification of alumin in an interscapular [between the shoulder blades] fibrosarcoma in 1991, a link was established between fibrosarcomas and vaccines. Many fibrosarcomas have then been described as "vaccine-associated". Actually, it would have been more accurate to say "injection-associated", since vaccination itself wasn't at stake. Although there're more post-inoculation reactions in cats than in dogs, fibrosarcomas should be put into perspective, their incidence being low - less than 0.003%.

Recommendations were made to practitioners, about vaccination sites among other things, and studies were undertaken and showed that, for the same products in use, there was a strong correlation with the veterinarian who had done the injection: in some practices, vaccinated cats never developed fibrosarcomas, whereas there were incidences in others. Personal practices were thus put at stake (shaken bottle or not, interference between alcohol and product, and so on). After several polemical years, it seems nowadays acknowledged that adjuvants do not have a significant influence on the development of fibrosarcomas.

To eliminate most of the identified risk factors, care should be taken to:

not mix several products in the same syringe;
properly homogenize the product to inject;
let the vaccine reach body-temperature before injection;
not use the same syringe as the one that pierced the seal.

^[1] Correct answers : 1. WRONG - 2. RIGHT