Vaccines and vaccination: Issues and controversies (Part 2) (Proceedings)

A. Vaccine Selection

Today, the list of licensed vaccines for just the dog and cat is large and diverse ...approximately 110 canine vaccines and 70 feline vaccines are available. Considerable differences among vaccines for the same antigen exist. The following FAQs center on scientific issues that should be considered when selecting vaccines for individual patients.

1. Should Modified-Live vaccines be selected over Killed vaccines?

When the option is available-yes. This is particularly true for cats.

      Killed (inactivated) vaccines

      1. Are less immunogenic than Modified-Live vaccines

      2. With the exception of killed rabies vaccine, require at least 2 initial doses in the absence of maternal antibody to immunize, then at least 7 to 10 additional days before protection is conferred.

      3. Contain an adjuvant.

      4. Tend to be more commonly associated with acute adverse events (especially pain and acute anaphylaxis) than MLV vaccine.

      5. Have been linked to vaccine associated sarcoma (VAS) in cats (especially, killed FeLV and killed Rabies).

      6. Cannot revert to virulence (i.e. cause the disease they are intended to prevent)...but, this "safety" issue may be offset by #4 above.

      7. Have the shortest duration of immunity.

NOTE: for some diseases, eg, leptospirosis, canine influenza, FIV, canine rabies, the only current option available is a Killed vaccine.

NOTE: Indications for the use of a Killed vaccine include: 1) vaccination of the pregnant patient (although one has to ask..."why is it necessary to vaccinate a pregnant dog or cat?") ...and 2) it is recommended that an immune compromised cat (e.g. FeLV and/or FIV positive) should only be vaccinated with a Killed vaccine. One could apply this rationale to all immune suppressed patients or patients regardless of the cause (e.g. chemotherapy). However...there are no scientific studies supporting this recommendation.

      Modified-Live (attenuated) vaccines

      1. Replicate in the patient post-inoculation and are therefore considered to be more immunogenic than Killed vaccines. A single dose will immunize in the absence of maternal antibody.

      2. May cause transient clinical signs and other potential safety issues (e.g. MLV Canine Distemper vaccine has been implicated in HOD in susceptible breeds). In puppies, MLV vaccines can produce transient (~5 to 7 days) suppression of cell mediated immunity that can be clinically significant in certain dogs.

      3. Do not contain adjuvant.

      4. Are more likely to induce "sterile" immunity than a Killed vaccine.

      5. Reversion to virulence of Modified-Live vaccine is technically possible with attenuated vaccine...actual occurrence is extremely rare with today's vaccines.

4. How does a Recombinant Vaccine compare to killed and modified-live vaccine?

Recombinant vaccines (and there are different kinds of recombinant vaccines) are the latest in vaccine technology used in humans and animals. In veterinary medicine, they are widely used throughout the US, Canada, Europe and the UK.

      Recombinant vectored vaccines

      1. Are considered to have the immunogenicity of Modified-Live vaccines; they are more immunogenic than killed vaccines.

      2. Are not adjuvanted (canine and feline)...note, some recombinant equine vaccines are adjuvanted.

      3. Are not capable of reverting to virulence because they only contain sequences of viral or bacterial DNA/RNA.

      4. Are Non-Replicating once injected into the patient.

      5. Do not induce immune suppression in vaccinates as do some MLV vaccines (esp. combination CDV + CAV-2 vaccines)...more on this issue under Core Vaccines (below).

5. Are there vaccines I should NOT select for use?

Yes-although the AAFP and the AAHA Vaccine Guidelines have categorized vaccines that are "not generally recommended" or "not recommended" (respectively), note that these are licensed vaccines; they are legal to administer in the US. Of all the vaccines categorized as "not recommended". Feline Infectious Peritonitis (FIP) and Canine Coronavirus vaccines are included because of the limited data available to demonstrate efficacy in a clinical setting.

Killed parvovirus and Giardia spp. vaccine were not recommended...these vaccines are discontinued.

When feasible, veterinarians should avoid adjuvanted vaccine in cats (all killed feline vaccines are adjuvanted) as a reasonable and recommended means of mitigating risk of vaccine-associated sarcoma (VAS).

6. Should I select 'combination' (ie, multivalent) products for my patients?

Immunologists will point out that the immune system of a healthy dog or cat is quite capable of responding to all of the combination antigens in vaccines on the market today. 3-in-1 and 4-in1 products are commonly used...but even 5-in-1 and 6-in-1 products are considered to be efficacious.

IMPORTANT: DO NOT MIX vaccines that are not specifically indicated by the manufacturer to be mixed.

7. When selecting vaccines for "kennel cough", which is recommended: Intranasal (IN) or Parenteral (SubQ)?

The IN (bi-valent) vaccine containing Bordetella bronchiseptica and parainfluenza virus is preferred over the parenteral (SubQ) B. bronchiseptica vaccine for the following reasons:

      a. Onset of immunity: dogs are protected within 72 hours following a single dose of the IN vaccine. On initial vaccination, 2 doses of the SubQ vaccine must be administered at a minimum of 2 weeks apart. Dogs are considered protected about 10 days following the 2nd dose.

      b. Duration of Immunity: based on challenge studies, the IN vaccines have been shown to protect dogs for 12-13 months following administration of a single dose. The duration of immunity for the SubQ vaccine is not known.

      c. Protection from shedding: Dogs immunized by the IN route do not shed bacteria if challenged; dogs vaccinated by the SubQ route do shed bacteria following challenge.

      d. Parainfluenza virus: IN inoculation provides superior protection against parainfluenza virus...all IN B. bronchiseptica vaccines contain MLV Parainfluenza virus. (NOTE: parenteral Parainfluenza virus vaccine provides minimal protection; therefore, IN inoculation is recommended by AAHA Vaccine Task Force.)

      e. Use of the 3-way IN vaccine containing Canine Adenovirus-2 (CAV-2) (in addition to B. bronchiseptica and parainfluenza virus) is NOT recommended. Parenteral inoculation of CAV-2 is recommended over the IN route.

B. Administration of Vaccine

The following FAQs address issues that pertain to vaccine administration and developing a protocol applicable to the patient population at risk.

Puppy and Kitten shots (i.e., the 'initial vaccine series')...what are the minimum and maximum intervals between doses?

Most authors agree...avoid minimum intervals of less than 2 weeks.1 Reason: vaccine-induced interference...the first dose could interfere with the 2nd dose if given, say, 1 week later. NOTE: this is NOT antibody interference and, as such, is NOT antigen specific...eg, a D-A2-P given this week and a Rabies given next week might result in failure of the Rabies vaccine to immunize.

In a puppy or kitten, what's the reasonable time (days-months) between vaccination and onset-of-immunity?

     • KILLED VACCINE-assuming no maternal antibody, 2 doses are required, 2 to 4 weeks apart, then about 10 days later (~ 24-25 days minimum)

     • MODIFIED-LIVE-assuming no maternal antibody, about 5 to 7 days post vaccination (earlier for some infections such as distemper).

     • RECOMBINANT Vectored-same as MODIFIED-LIVE. Exception: The recombinant canine distemper virus (rCDV) vaccine has been shown to immunize dogs in the presence of maternal antibodies. rCDV is indicated in high exposure risk environments.

IMPORTANT: When should the last dose of vaccine, in the initial series, be given?

For both the dog and cat, all Guidelines (AAHA, AAFP, and WSAVA) recommend 14-16 weeks of age. The rationale behind these recommendations is to insure that interfering levels of maternal antibody are not circulating at the time the last dose in the initial vaccine series is administered. Several manufacturers now list earlier completion times (eg, 12 and 13 weeks in the US; 10 weeks in the UK and Europe). Such practice is NOT recommended.

How many doses of vaccine should be given to a dog or cat presented for their initial vaccine series if the patient is older than 15-16 weeks of age?

Most veterinarians recommend administering 2 doses, 3 to 4 weeks apart.

      Can I reduce the volume (e.g. from 1 mL to 0.5 mL) of vaccine when inoculating a toy breed dog?

No-doing so may leave the toy breed (small dog) susceptible for one or more of the diseases you're trying to prevent. In the case of RABIES, reducing the volume is equivalent to NOT IMMUNIZING the patient. In some locations, doing so could represent medical malpractice or a breach in the Standard of Care. ("Small Breed" dogs are generally considered to be those that weigh less than 20 pounds of weight as adults)

      Can I mix vaccines from different manufacturers?

No-NEVER do this in the same syringe! On the other hand, vaccines from different manufacturers may be administered at different sites in the same patient at the same visit.

      Once reconstituted, how long can a Modified-live vaccine dose be stored at room temperature and still be safe/effective?

It varies-canine distemper and feline herpesvirus-1 vaccine can lose immunizing capability within 2-3 hours. Parvovirus vaccines (canine and feline panleukopenia), on the other hand may be stable for a few days. RECOMMENDATION: For all MLV vaccines...reconstitute and use within 1 hour. If not used within 2 hours...discard the product.

      Can I give a parenteral vaccine dose and, at the same visit, give an intranasal vaccine dose for the same disease(s)?

Yes...this is done routinely. For example, administering a parenteral D-A2-P-P (distemper-adeno-2-parvovirus-parainfluenza) plus an intranasal "kennel cough" vaccine (which usually contains Bordetella + parainfluenza virus) inoculates the patient with 2 doses of parainfluenza virus. While it might seem that the patient would derive a superior immune response consisting of both a circulating humoral immune response (IgG) + a local immune response from the intranasal vaccine (secretory IgA), there is minimal evidence that doing this might be beneficial in an individual dog.

      Can a vaccine intended for intranasal administration be effectively given parenterally, for example, SQ administration of an intranasal B. bronchiseptica + parainfluenza?

NO! This MUST NOT be done. Severe post-vaccination complications associated with replication of bacteria and release of toxic proteins that target the liver could cause acute hepatocellular injury and death following a single dose. WARNING: some products licensed for IN administration are packaged as though they are intended for parenteral administration. ALL PERSONNEL AUTHORIZED TO ADMINISTER VACCINE MUST BE TRAINED ON PROPER ADMINISTRATION TECHNIQUES.

      Can a vaccine licensed for intranasal administration be effectively administered orally to a patient that resists intranasal administration?

No-administering these vaccines by the oral route results in rapid inactivation of the vaccine without immunization.

      Are antibody titers a valid assessment of immunity?

Depends! ...specific limitations apply to titers when assessing the immune status of an individual patient. First, titers for CDV, CPV, and feline parvovirus (panleukopenia) correlate extremely well with immunity...dogs/cats that have a "positive" titer are considered immune. Second, a "negative" titer does not always correlate with susceptibility. Antibody is a glycoprotein and does dissipate over time. However, immunologic "memory" (B-lymphocytes) is retained for many years for these 3 diseases. Exposure to virulent virus in a previously vaccinated, antibody negative patient typically results in a rapid anamnestic 'boost' of antibody titer and a protective immune response. Annual or triennial boosters are merely a form of immunologic insurance for these 3 diseases. Most animals don't need it.

For other diseases, antibody titers are not good correlates of protective immunity. Feline herpesvirus-1 and feline calicivirus titers can be obtained, but are not recommended for the assessment of the individual patient's immunity to those diseases. FeLV titers are not valid at all because of the lack of a valid test method. Leptospirosis titers are routinely performed but generally are used to define exposure/infection...not immunity. See RABIES TITERS (next question).

      Can rabies titers be used to assess immunity in a dog or cat subsequent to vaccination?

No. States/local municipalities generally do not accept FAVN (fluorescent antibody virus neutralization) rabies titer results as a replacement for vaccination or as means of assessing immunity in a dog/cat that has been involved in a bite incident. FAVN test results (only provided in the US by Kansas State University and DoD [military members only]) are used to comply with requirements on the exportation of animals to designated Rabies-Free areas.

COST: $47 (2009 price); takes 2-3 weeks.

Attn: FAVN Rabies Laboratory

Kansas State Veterinary Diagnostic Laboratory

Mosier Hall O-245

1800 Denison Avenue

Kansas State University Phone: 785-532-4483

Manhattan, KS, USA 66506-5601 Forms: www.vet.ksu.edu/rabies

      When would an antibody titer be indicated in an individual patient?

     • To determine whether or not a puppy or kitten was immunized following administration of the initial vaccine series, a titer can be submitted 2 or more weeks following the last dose of the initial series.

     • To assess whether an adult animal has maintained an antibody titer (CDV, CPV, Feline parvovirus) following previous vaccination (e.g., years earlier, with no recent revaccination).

     • Veterinarians may elect to determine titers, rather than administer booster vaccines in patients with a history of having had a vaccine reaction -or- having been treated for and recovered from an immune-mediated disorder (e.g., hemolytic anemia or thrombocytopenia) can be tested.

      If an adult dog/cat has exceeded the recommended booster interval by several months is it necessary to administer 2 doses of vaccine, 3 to 4 weeks apart, before considering the patient "immunized"?

No. A single booster dose (MLV vaccine being preferred), is likely to be sufficient assuming the patient was vaccinated at some point earlier in life..up to 3 years. Immunologic "memory" is the reason.

Overdue for RABIES: In the event a dog or cat has exceeded the vaccination interval required by State or local statutes for RABIES, a single dose is still all that is required to 'boost' the patient...immunologically speaking. Legally speaking, however, it's always wise to check the official position of your State by contacting the State Dept of Public Health or the State Public Health Veterinarian.

C. Core Vaccines

     • AAHA Canine Core Vaccines: distemper (CDV), adenovirus-2 (CAV-2), parvovirus (CPV) and rabies.

     •AAFP Feline Core Vaccines: feline parvovirus (feline panleukopenia virus or FPV), herpesvirus-1 (FHV-1), calicivirus (FCV), and rabies.

      Are Dobermans and Rottweilers still unlikely to respond to Parvovirus vaccination?

Today, most agree that these breeds do NOT have a uniquely higher risk of acquiring parvovirus following exposure nor are they more likely than any other breed to fail to be immunized following vaccination. The high disease incidence and the frequency of vaccine failures recognized in the late 70's and early 80's is no longer an issue in the US.

      Does the new "strain" of canine parvovirus (CPV- 2c) warrant the use of a new vaccine or a specific vaccine brand already on the market?

No. First, CPV-2c is not a new 'strain'...it's a biological variant of parvovirus that has emerged as part of the normal 'genetic drift' of the virus. The changes in the virus are limited to a small number of nucleotide base-pairs. CPV-2b is still most prevalent in the US, but CPV-2c is being reported. It's actually been around 10 years since it was first reported in Europe.

Consider the following FACTs:

     • CPV-2c has similar or less virulence than CPV-2a or -2b.

     • ALL of the current vaccines provide comparable protection against a CPV-2c challenge.

     • ALL of the current vaccines provide comparable duration of immunity against a CPV- 2c challenge.

     • The IDEXX SNAP test for parvovirus antigen (feces) will detect any of the parvovirus variants.

In other words...the emergence of CPV-2c in the US poses NO need to change either vaccines or vaccination schedules.

      Is there any advantage to using the recombinant canine distemper virus (rCDV) vaccine over conventional MLV vaccines? (There are NO killed distemper vaccines)

Yes-particularly in young dogs and dogs considered to be at risk of exposure to CDV.

In adult dogs, rCDV and MLV act very much alike.

In puppies, there are some important differences:

     • A single dose of rCDV vaccine has been shown in studies to protect puppies against a same-day challenge. MLV vaccine can only achieve such rapid immunity in the absence of maternal antibody.

     • A single dose of rCDV has been shown in studies to immunize puppies in the presence of maternal antibody. Maternal antibody can interfere with MLV CDV vaccination for as long as 12-14 weeks.

     • IMPORTANT: all MLV vaccines (particularly in combination with CAV-2 vaccines) are known to induce transient immune suppression beginning about 3-days post-inoculation and lasting about 5 days...clinical illness (local to generalized demodecosis; sub-clinical to clinical tracheobronchitis "kennel cough") may result. rCDV vaccines do not cause immune suppression.

      Are Non-Adjuvanted Feline vaccines still recommended over Adjuvanted?

Yes-the AAFP Advisory Panel that authored the Feline Vaccine Guidelines (2006) has suggested veterinarians should avoid the use of inflammatory vaccines whenever possible...that statement was specifically intended to address adjuvant-induced inflammation.

Adjuvants, by their very nature, induce inflammation, typically...chronic inflammation lasting days to weeks. The cellular response associated with adjuvant-induced inflammation is still regarded by most oncologists and other academicians who work with vaccines to be responsible for the DNA injury (oxidative injury) associated with metaplasia in fibroblasts. In genetically pre-disposed cats (it appears), there is risk of neoplastic transformation of fibroblasts into fibrosarcoma (or other types of mesenchymal tumor) . BE PRACTICAL...avoid adjuvanted vaccines in cats!

D. Non-Core Vaccines

Although vaccination recommendations for CORE vaccine are widely accepted, decisions regarding administration of vaccines considered to be NON-CORE are generally associated with much more controversy. The following FAQs address many of these controversies.

      Is an intranasal vaccine for Bordetella bronchiseptica better or worse than the injectable vaccine?

The studies are clear. Both vaccine types effectively mitigate the signs of infection. There are some differences that favor use of the intranasal vaccine:

     • Almost all IN vaccines contain parainfluenza virus vaccine (there's only one that does not); the SQ vaccine does not. (IN is the preferred route for parainfluenza vaccine).

     • The onset of protection is much faster with the IN vaccine (~3-5 days). The SQ vaccine requires 2 initial doses...about 10 days later immunity is conferred (3 weeks +).

     • The IN vaccines have a duration of immunity that is 12-14 months (based on challenge). We don't know the DOI of the SQ vaccine.

     • ONLY the IN vaccine prevents shedding of B. bronchiseptica following exposure in the vaccinated patient...very important in multi-dog environments.

      When is the parenteral (SQ) B. bronchiseptica vaccine indicated?

It's indicated when the patient will not tolerate IN administration...don't fight the patient.

      Is there any new information pertaining to Leptospirosis vaccines?

By Fall of 2010, it is anticipated that ALL manufacturers will have a 4-way leptospirosis vaccine. Licensure of vaccines containing more that the current 4 serovars is NOT anticipated. While there are some differences in the manufacturing process of each vaccine, they are all killed bacterins. Interestinly...all of these vaccines are considered to effective in presenting clinical disease for 12 to 14 months). One product is not adjuvanted. There are no live or recombinant leptospirosis vaccines.

      Do Lyme disease vaccines work?

Yes. The published data is clear on the fact that the commercial vaccines for Lyme disease do a relatively good job of protecting dogs...for about 12 months. Don't expect 100% of the patients vaccinated to become immunized. Two vaccine types are on the market: a killed, whole spirochete and a recombinant OspA (outer surface protein-A). All vaccines depend on the same antigen, OspA, to immunize. There is NO advantage in using a killed vaccine over the recombinant Lyme vaccine...the newest Lyme disease vaccine is a killed vaccines that provides additional antigens (OspC) and therefore claims added protection against Lyme disease. However, the value of OspC-expressing spirochetes in this vaccine has not been demonstrated in dogs. Killed, whole spirochete vaccines appear likely to cause more post-vaccinal reactions than the recombinant vaccine.

None of the vaccines used in the US today cause a False '+' test result on the IDEXX 3Dx or 4Dx test for Lyme borreliosis.

Vaccines should NOT be used as part of the treatment for Lyme disease!