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vaccines titers memory cells
#1
Vaccines and Titers
What Vets are NOT telling YOU
Specific immunologic reactivity is often used for diagnostic purposes. Serologic testing for infectious agents or for an antibody response demonstrating exposure to an infectious agent is one of the most common ways immunologically based tests are used in clinical medicine. Immunologic testing is also used to evaluate the immune system itself in cases of suspected hypersensitivity or autoimmunity, to estimate resistance to a particular disease, or to document an immunodeficiency state. Tests of immune competence are used for two main purposes. One is to check if an animal will be protected from a particular infectious disease, and the other is to see if an animal has a congenital (or acquired) immunodeficiency state. Because of concerns about adverse vaccine reactions, veterinarians are interested in evaluating individual animals for adequacy of protection rather than simply administering booster vaccines. This is often done through the measurement of serum antibody titers. Although such titers may provide a rough correlate with protective immunity for certain viral infections, this is merely a correlation. Vaccine induced protection often relies on cell mediated or other aspects of immunity in addition to humoral immunity. Antibody titers don’t provide information relative to cellular immunity. Animals with “negative” titers may well be protected from disease, and conversely, animals with “positive” titers may be susceptible to disease. These titers are best used only for disease in which titer has been demonstrated to at least roughly correlate with resistance to disease challenge (feline and canine parvo, distemper, feline viral respiratory). Additionally, since prevalence of protection by vaccination should be high, negative predictive value of even sensitive and specific testing is low, meaning that many animals with negative titers are “false negatives” and are truly protected from disease.
 
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 when first presented?
Most veterinarians recommend administering 2 doses, 3 to 4 weeks apart. However, it should be noted that when using a MLV or recombinant CORE vaccine, administration of a single dose in an unvaccinated dog/cat that is older than 16 weeks of age is likely to produce a protective immune response. REASON: MLV and recombinant (canine distemper only) vaccines will replicate following inoculation; therefore, a single dose will both „prime‟ and „immunize‟.
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
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 immunemediated disorder (e.g., hemolytic anemia or thrombocytopenia) can be tested.
If an adult dog/cat has exceeded the recommended booster interval for the CORE vaccines by several months is it necessary to administer 2 doses of vaccine, 2 to 4 weeks apart, before considering the patient to be effectively “boostered”?
 Usually not. A single booster dose (MLV [or Recombinant CDV] vaccine being preferred), is likely to be sufficient assuming the patient was vaccinated at some point earlier in life. Immunologic “memory” is the reason.
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.
In several studies, canine distemper virus titers and canine parvovirus titers suggestive of resistance were detected in >95% of the dogs tested, respectively. Canine parvovirus vaccines may provide life-long immunity and distemper virus titers are detected for up to 10 years in many dogs. Thus, in low risk dogs, modifi ed live DA2PP vaccines should be administered no more often than every third year. In addition to serological studies, challenge studies from several vaccine manufacturers have shown at least 36- 57 week duration of immunity to infectious canine adenovirus, distemper, and parvovirus on challenge. Positive serologic tests for canine distemper virus, canine adenovirus 1, and canine parvovirus are predictive of resistance. If validated assays are available, serological testing for prediction of these vaccine antigen needs appears to be appropriate for use in lieu of arbitrary vaccination intervals.
WHAT IS THE ACTUAL DURATION OF IMMUNITY (DOI) FOR EACH CANINE VACCINE?
Unfortunately DOI is a very complex issue involving the particular antigen used, MLV vs. killed various manufacturing techniques, the individual patient's response to the vaccine, the age of the patient, and the number of vaccines given.
Traditionally veterinarians have relied on the vaccine manufacturers to provide the DOI data to the profession. Neither the maximum nor minimum duration of protective immunity of most canine vaccines are known. Unfortunately the one-year recommendation for most canine vaccines was not determined by any scientifically validated study. Except for rabies vaccination, we don't know the exact duration of immunity for most current canine vaccines produced because most DOI studies are based on one year serum titers and not on timed experimental challenge. Plus not all of the dog breeds would be represented in a DOI study. Lastly most vaccinated animals are never challenged because the pathogens are never present in the animal's environment. Therefore every vaccine appears to be 100% efficacious when there is no challenge!
 
WHAT RECENT DATA SUPPORT EXTENDED VACCINATION INTERVALS?
Recently the first peer-reviewed studies that approach duration of immunity (DOI) issues in small animal medicine from a seroepidemiologic standpoint were published in JAVMA. In those studies, hundreds of dogs and cats that had been vaccinated at various intervals prior to enlistment into the study served as subjects to address the question of the duration of the serologic response induced by two combination vaccines; one for dogs, and one for cats. In other words, if an animal was vaccinated 1, 2, 3, or 4 years ago, what is the serologic response now for the major antigens? For all the antigens tested, serologic responses remained within protective levels, according to the “cut-off” values established by Cornell University, for the majority of dogs and cats up to 4 years after vaccination. Another parameter measured in the studies concerned the memory response. One of the simplest ways to measure memory and memory response is to stimulate an animal with an antigen or infect it with an agent. A significant (4-fold increase) response within 4 or 5 days after that challenge or exposure indicates a memory response, not a primary immune response. This is a simple and elegant way to measure whether or not memory cells exist. Therefore, these data indicated that a serologic response can be measured for years after an initial vaccination series, and that animals can be shown to have memory cells, probably T and B cells, for the same period of time. This is the first time that such data have been published in refereed veterinary literature. In another recently published study laboratory beagles that had been vaccinated three years previously with a combination modified-live viral vaccine experienced less severe clinical disease when challenged according to USDAmandated procedures. These data are similar to those reported in the unpublished trade “literature” with at least one other new combination viral vaccine. These recent data suggest that currently available vaccines may confer immunity for more than 1 year. The question is, where do these novel studies using relatively small numbers of experimental subjects fit into the big picture of vaccineinduced duration of immunity at the population level?
MY CHILD ISN’T VACCINATED EVERY YEAR, HOW COME YOU’RE TELLING ME MY DOG SHOULD BE?
The issue of children not receiving vaccinations every year has been raised as evidence for why dogs and cats do not need annual vaccinations. While the immune systems of all mammals are similar, humans, by virtue of their living in “large herds” are constantly exposed to a whole variety of microbes, which, no doubt, extends the duration of immunity by providing the opportunity for “free vaccination” that results from natural exposure to clinical and subclinical infections, such as measles and Bordetella pertussis. The same level of natural exposure is probably not as likely to occur in dogs and cats that live, increasingly, in isolation from other members of their species. Dogs evolved as a herd species, much like humans, and their immune systems evolved in the context of constant interaction with microbes. This is a very different scenario than currently occurs, for instance in dogs living as isolated members of a human family in an apartment building. Our counterparts in human medicine have tremendous resources, both human and financial, to deal with these issues related to duration of immunity. These resources are not available to the veterinary practitioner, and veterinarians do not achieve the same level of detail in animal vaccination studies as that found human studies. In addition, no good mechanism for reporting disease in veterinary medicine, that is, for understanding prevalence and incidence, currently exists. This makes it difficult to assess vaccine efficacy from an epidemiological standpoint in veterinary medicine
WHAT IS THE CRITICAL EXPERIMENT TO DETERMINE WHICH VACCINATION PROTOCOL IS THE CORRECT ONE? DO WE REALLY NEED ANNUAL VACCINATION?
If the definition of need is to produce the result of better clinical immunity, or reduction of morbidity, then the answer is not known. No one has actually tested the correct hypothesis, although expert opinions have been offered. What has been tested to date is the difference between no vaccination and, for example, triennial vaccination. Not surprisingly, some benefit can be shown with triennial vaccination, compared with no vaccination. For the past 20 to 30 years, veterinarians have recommended annual vaccination and checkups. This practice has been associated, most likely causally, with dramatic reduction in the prevalence of infectious diseases. The real test, therefore, should be determining the difference between annual vaccination and triennial vaccination. In reality, then, the proposal to alter successful vaccination protocols is a large experiment; a big “field trial” using clientowned animals. Although it is believed that protocol change will not result in reduced vaccine efficacy, the outcome is truly unknown. What is known is that most pathogens are endemic at some level in populations, and are likely to reappear, clinically, as soon as herd immunity diminishes. What is also known is that vaccination as practiced now works incredibly well with very few adverse reactions, but a critical experiment has been proposed in the form of modified vaccination protocols. The question then becomes are veterinarians and, by extension, their clients willing participants in this experiment. The reality is DOGS owned in isolataion have a lower immunity response to those kept in packs , also they have become experimental when it considers vaccines ! Something clients will not know or understand .
The primary goal of vaccination is the induction of long-lasting and protective immunity. During the initial stages of pathogen challenge, innate immune responses are induced that may provide nonspecific clearance of the challenge. However, in addition to providing immediate protection, innate immune mechanisms also initiate adaptive immunity in the event that memory responses are required for longterm immune protection. The fundamental goals of a successful vaccine program are to safely induce immunity that provides antigen specific protection that is efficacious and long lasting. Effective immunity requires interplay between host immune mechanisms and pathogen challenge. The initial element of host protection from such a challenge involves innate immune mechanisms. Disruption or penetration of superficial epithelium and/ or mucosal barriers will result in pathogen exposure to host immunity. If immune clearance is ineffective, the potential for disease development exists. Beneath the superficial epithelium lies components of the innate immune system, which provides the host with a well-orchestrated collection of immune mechanisms that will target non-self constituents that are typically encountered during early and acute stages of pathogen challenge. If the challenge is low-grade, innate mechanisms may completely eliminate the challenge. Among the constituents of innate immunity are leukocytes that express surface proteins capable of directly signaling additional cells or secreting protein factors that will arm the host to be protected during the course of pathogen interaction. The presence of invading pathogen is initially detected by sentinel cells that include macrophages, dendritic cells (DCs), and mast cells. These sentinel antigen presenting cells are highly capable of recognizing invading pathogen due to the presence of surface protein receptors. These receptors bind with pathogen via their pathogen associated molecular patterns (PAMPs). Pathogen associated molecular patterns are expressed by a variety of pathogens such as bacteria, fungi, and viruses. Since pathogens mutate at a rapid rate, the receptors that can identify invading pathogens do not specifically identify individual microbes but rather can identify classes of pathogens that result in a global host response. Receptors on sentinel cells are referred to as pattern recognition receptors (PRRs), which may be classified into four separate categories. Pattern recognition receptors may be secreted, free receptors located in the extracellular space and in general circulation; PRRs may be membrane bound and phagocytic in function; PRRs may also be membrane bound and responsible for cellular signaling; or they may be cytoplasmic in their location. A primary example of host PRR includes the toll like receptors. Examples of PAMPs include Gram negative lipopolysaccharide (LPS), Gram positive peptidoglycan, and acid fast bacterial glycolipids. These molecules are unique to classes of microbial pathogens and are not expressed by mammalian species, which therefore provides a mechanism for host identification of pathogen challenge. Binding of PAMP with PRR results in cellular activation to trigger inflammation and other innate immune pathways. Immunologic members of the adaptive (memory) immune response include antigen presenting cells, lymphocytes, and cytokine mediators. Collectively, these constituents provide effective clearance of pathogen challenge conferring immunologic specificity and memory. Antigen presenting cells include dendritic cells, macrophages, and B lymphocytes. Dendritic cells are the most efficient antigen presenting cells, as they are the only cells that can present antigen and effectively activate naïve T lymphocytes . Immature DCs are located throughout the host, and they are specifically designed to capture foreign antigen. Once stimulated by foreign antigen, DCs mature and become highly effective with regard to antigen presentation to host T cells. In order to effectively express antigen, DCs must express surface major histocompatibility molecules (MHC) class II molecules, which are essential for propagation of this process. Dendritic cells ingest foreign antigens, process antigen in an efficient manner, and present peptides within MHC II to T cells, via the T cell receptor. Macrophages are an additional antigen presenting cell, but because they have the capacity to destroy ingested material, they are less efficient with regard to antigen presentation when compared with DCs. B lymphocytes also have antigen presenting capabilities and are highly effective during a secondary immune response. Dendritic cells are divided into two categories, classified as myeloid and plasmacytoid. Plasmacytoid dendritic cells are particularly important for immunity and are major producers of type I interferons, such as interferon alpha and beta, which demonstrate pronounced antiviral properties. Lymphocytes are found within lymphoid organs, in circulation, and scattered under mucosal surfaces. Although they morphologically appear similar, they are characterized by their cell surface molecules and their behaviour. The pattern of cell surface molecules defines their specific immunophenotype. Through the process of immunophenotyping, it is possible to identify many lymphocyte subpopulations. Helper T cells possess antigen receptors (TCRs) that consist of two peptide chains. These receptors have an antigen binding groove that can bind to antigenic peptides linked to major histocompatibility complex molecules on antigen presenting cells. The antigen binding chains of the TCR are linked to a complex signal transducing component called CD3. Each TCR is associated with either CD4 or CD8. CD4 binds to MHC class II molecules on the antigen presenting cell. CD8 binds to MHC class I molecules expressed on all nucleated cells. In order to respond to antigens, T cells must bind to antigenic peptides within the MHC protein cleft. In addition, they must also receive co-stimulation from cytokines and other co-stimulatory molecules. The signals from an APC to a T cell are communicated through an immunological synapse. There are three major types of helper T cell subpopulations (Fig. 2). Th1 cells are stimulated by interleukin 12 and secrete interleukin (IL)-2 and interferon gamma. This response classically leads to a cell-mediated immune response. Th2 cells are stimulated by IL-1 and secrete IL-1, IL-13, and IL-10. This signaling pathway generally leads to antibody production. Th17 cell development is stimulated by IL-6, transforming growth factor beta and IL-23. This cell population secretes IL-17 and promotes neutrophilic inflammation. Cytotoxic T lymphocytes are activated CD8 expressing T lymphocytes that are essential for effective clearance of virally infected or altered self cells. Cytotoxic T cells are an important component of cell-mediated immunity. The requirements for generating protective immunity vary with the nature of the infecting organism. Many effective vaccines work by inducing antibodies targeted toward specific pathogens. For many pathogens, including extracellular organisms, antibodies can provide protective immunity. This is not the case for all pathogens, however, such as intracellular viruses, which may require additional cell-mediated immunity that is provided by activated CD8 T lymphocytes. Effective protective immunity against microorganisms requires the presence of preexisting antibody at the time of infection. Antibody proteins will aid in preventing damage from the presence of the organism or prevent infection altogether. An example of protection involves tetanus vaccination, which provides antibodies that bind even low levels of exotoxin liberated at that time of challenge. An added mechanism by which antibody proteins provide protection at the time of challenge includes the production of neutralizing antibodies. Neutralizing antibodies are capable of preventing infection by viral pathogens.
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