vaccines

primary immune response

occurs the first time a specific antigen is identified by

either T or B lymphocytes. Following initial exposure to an antigen, there is a delayed primary

response in antibody production. This delay, known as the lag phase, is due to the process-

ing of antigen. In time, B cells differentiate into plasma cells capable of producing antibody.

The primary response typically takes 10 to 14 days for relatively small amounts of antibodies

to be produced. As the antigen-bearing pathogen is destroyed, the number of antibodies in

blood declines because the plasma cells die, marking the end of the primary response. The

antigen-stimulated B cells that did not differentiate into plasma cells now become memory B

cells.

secondary or anamnestic immune response.

Memory B cells remain dormant in lymphatic tissue until subsequent exposure to the

same antigen. Activated memory B cells will differentiate rapidly (approximately one to three

days) and will produce large amounts of antibodies. This more rapid response and increased

production of antibody following subsequent exposure to the same antigen occurs because so

many more cells are able to recognize and respond to the antigen

vaccine

comes from latin word vacca cow. the cowpox virus was the first immunization against smallpox. its easier to induce protection against viruses than bacteria

Animal and Plant Health Inspection Service Center for Veterinary Biologics (APHIS-CVB)

responsible for regulation of veterinary biologics (vaccines, bacterins, antisera, diagnostic kits) by ensuring these products are pure, safe, potent, and effective through enforcement of the Virus Serum Toxin Act. They monitor adverse reactions to biologics. An adverse event involving a biologic product should be reported to the manufacturer and then by contacting the CVB.

maternal antibodies

can interfere with vaccine booster immunity. will fall to nonprotective levels by two to three months of age but will still interfere with boosters until 6 months of age

 Depot adjuvants

 

protect antigens from rapid degradation, thus contributing to a prolonged immune response.

Examples of depot adjuvants are aluminum phosphate, aluminum hydroxide, alum, and Freund's incomplete adjuvant (water-in-oil emulsion

Particulate adjuvants

deliver antigen in such a way that both cell-mediated and humoral immunity are enhanced by stimulation of antigen processing. Examples of particulate adjuvants are liposomes and microparticles

Immunostimulatory adjuvants

promote the production of cytokines (proteins that help mediate cellular interaction and regulate cell growth and section). Immunostimulatory adjuvants stimulate macrophages, lymphocytes, or antigen processing. Examples of immunostimulatory adjuvants are lipopoly-saccharide, glucans, dextran sulfate, and complex microbial products such as the anaerobic bacterium Corynebacterium sp.

Mixed adjuvants

combine a particulate or depot adjuvant with an

immunostimulatory agent. An example of a mixed adjuvant is Freund's complete adjuvant (killed

Mycobacterium tuberculosis incorporated into water-in-oil emulsion)

 If bacteria are the microbe inactivated (killed)

the vaccine is known as a bacterin. Bacteria are usually killed with formaldehyde and incorporated with alum or aluminum hydroxide adjuvants. Because the bacteria in bacterins are dead, the immunity produced is relatively short, usually lasting no longer than one year and sometimes less. Examples of diseases in which bacterins are used include swine erysipelas (Erysipelothrix rhusiopathiae) and strangles (Streptococcus equi).

Toxoids

a special type of vaccine used to stimulate an active immune response against toxins instead of microorganisms. The toxin is inactivated by heat or chemicals (mainly formaldehyde) but is still able to stimulate antibody production. Toxoids have shorter durations of effectiveness than other vaccines and usually contain adjuvants and preservatives. Toxoids are usually incorporated with an alum adjuvant such as aluminum hydroxide and are available for most clostridial diseases and infections caused by toxigenic Staphylococcus spp. An example of a toxoid is tetanus toxoid used in the immunization against tetanus caused by Clostridium tetani.

subunit vaccine

only part of the microorganism is used to provoke immunity. were developed to identify and isolate the most important antigenic part f the microorganism-the part needed to produce the desired immune response-and eliminate the antigenic parts that do not contribute to providing protective immunity, can cause adverse reactions, or may interfere with the immune response. An example of a subunit vaccine is the E. coli vaccine, which contains the pilus (an attachment structure on the cell wall of some bacteria) antigen that allows the animal to produce anti-pilus antibodies to prevent bacterial attachment to the intestinal wall.

Attenuated

vaccines

contain microorganisms that go through a process of losing their virulence (called atten-

uation). The microorganisms are altered so that their virulence is reduced; however, they must be

able to replicate within the patient to allow the vaccinated animal adequate exposure to the agent

to develop specific immunity. The level of attenuation is critical to the success of these vaccines;

underattenuation will result in residual virulence and disease, while overattenuation will result in

an ineffective vaccine. Microorganisms are made avirulent through genetic manipulation, growth

on media or cells to which they are not naturally adapted, prolonged culture in tissue or animal

embryos, or the use of chemicals. One way attenuated microorganisms are made less virulent is to

grow them in media containing adjusted levels of chemicals that trigger and enhance mutations of

that microorganism. These mutations change the microorganism's metabolism in a way that alters

its ability to cause disease. have better efficacy (they can be effective without adjuvants, which

decreases the risk of vaccine reactions) and produce quicker stimulation of cell-mediated immunity

man killed vaccines. Disadvantages of attenuated vaccines include possible abortion when given to pregnant animals, and some attenuated vaccines can produce mild forms of the disease and can he

shed into the environment.

Temperature-sensitive vaccine microorganisms

lose their ability to grow at the animal's normal core body

temperature, but they can grow at other temperatures (like the cooler temperatures of the ocular or

nasal mucosa). Attenu-

ated vaccines are typically freeze dried and need to be reconstituted prior to administration

Chemically altered microorganisms

are safer than unaltered live microorganisms,

and they produce the same level of immunity, but the duration of the immunity is shorter

 microorganisms passed through cell cultures or embryos

with each passage, the microorganisms are subject to mutations that make them less virulent. Some microorganisms are passed through more than 100 different cell cultures or embryos. Animals mount an immune response to attenuated vaccines, but the vaccines do not usually produce disease. Attenuated vaccines stimulate both cell-mediated and humoral immunity better than killed vaccines; therefore, the immunity produced by attenuated vaccines usually lasts longer than immunity produced by killed vaccines and fewer doses are needed to achieve active immunity

modified-live virus (MLV) vaccines

An example of a MLV vaccine in dogs is canine parvovirus vaccine. Another example of a MLV vaccine is the Orf vaccine in sheep, which must be handled carefully due to its potential to cause zoonotic disease in people. Inappropriate handling of vaccines may lead to their inactivation. Vaccines (especially MLVs) are sensitive to sunlight, excessive heat, and freezing. Vaccines should be ordered from a reputable company that delivers them in shipments with cold packs. Upon delivery, vaccines should be unpacked and stored in the refrigerator. Frozen vaccines may have experienced cell death, and overheated vaccines will have been rendered inactive.

avirulent-live vaccines

example of an avirulent-live vaccine in cattle is Brucella abortus RB51 vaccine, which must also be handled with great care due to the possibility of zoonotic disease initiation in humans after accidental exposure.

Recombinant vaccines

a gene or part of a microorganism's DNA or RNA is isolated and removed from one

organism (usually the pathogen) and inserted into the DNA (or RNA) of a nonpathogenic microor-

ganism (referred to as the vector). The microorganism's genetic material is "recombined" to make

something new. The advantages of recombinant vaccines include fewer adverse effects, effective

immunity, and varied routes of administration. Increased cost is a disadvantage.

Antigens generated by gene cloning (category l)

Recombinant genes (DNA) coding for a

surface or other molecule are isolated from the pathogen. This DNA is then inserted into a

nonpathogenic cloning vector (bacterium, yeast, or other cell), and the recombinant antigen

is expressed. This technique yields large amounts of purified antigen that can be used in a

vaccine. The first successful use of gene cloning to prepare an antigen in this way involved

the foot-and-mouth disease virus. An example of a vaccine using antigens generated by

gene cloning is the Lyme vaccine that uses a purified subunit outer surface protein (OspA)

encoded by a Borrelia burgdorferi gene.

Genetically attenuated organisms (category II)

Genes may be deleted from a pathogenic micro-

organism modifying its genes so that the bacterium becomes irreversibly attenuated. Gene

deletions can also result in the microorganism's inability to replicate so that it cannot cause

disease. These genetically altered microorganisms are then used to produce a vaccine. This vac-

cine stimulates the immune response, yet has a low risk of producing the disease. An example

of a vaccine developed from gene deletion is the pseudorabies virus vaccine for swine.

Live recombinant organisms (category III)

Microorganisms may have select parts that stim-

ulate the immune response. Genes that code for those select parts can be inserted into a

recombinant organism to produce a vaccine containing only the antigenic part or the recom-

binant microorganism. The first category III vaccine approved by the USDA was against the

Newcastle disease virus for poultry.

Polynucleotide or DNA vaccines

directly inject DNA that encodes for foreign antigens into bac

terial plasmids (circular pieces of DNA located outside the chromosome) that act as vectors

ahen the genetically engineered plasmid is injected intramuscularly into an animal, it may be

Wen up by host cells where the DNA is transcribed into mRNA and translated into endogenous

tarcine protein. Transfected host cells express the vaccine protein allowing the animal to develop

vautralizing antibodies and cytotoxicT lymphocytes. Polynucleotide vaccines are ideal for those

ncroorganisms that are difficult or dangerous to grow in the laboratory. An advantage to poly-

mucleotide vaccines is that it is possible to select only the genes for the antigen of interest. DNA

uaccine examples are feline immunodeficiency virus (FIV) vaccine and canine melanoma vaccine.

Antitoxins

substances that contain antibodies (immunoglobulins) obtained from an animal

that has been hypersensitized to neutralize toxins. The immunity produced by an antitoxin is short

lived because the immunity rendered is passive. Antitoxins may also contain preservatives that

can cause adverse reactions. An example of an antitoxin is tetanus antitoxin. Tetanus antitoxin is

obtained by injecting Clostridium tetani toxins that have been denatured and made nontoxic by

treatment with formaldehyde into donor horses, allowing time for antibody levels to rise in these

horses, collecting blood, separating plasma from the blood cells, and using the protein that con-

tains the antibodies to the toxin for passive immunization. Tetanus antitoxin is given to animals

when they are at risk of developing tetanus secondary to a contaminated deep puncture wound.

Antiserum

antibody-rich serum obtained from a hypersensitized or infected animal. Antiserum

is produced in a similar fashion as antitoxin except that antibodies are collected from the plasma.

The immunity produced by antiserum is immediate but short lived because the immunity rendered

is passive. Antiserum may also contain preservatives that can cause adverse reactions. Examples

of antisera developed for animals are canine distemper, feline panleukopenia, and bovine anthrax.

Autogenous vaccines

produced for a specific disease problem in a specific area. For example,

an organism may be isolated from an affected animal on a farm where an infectious disease out-

break is occurring and made into a vaccine for that specific farm. The microorganisms are grown

in culture, killed, and mixed with an adjuvant. These vaccines may contain endotoxin and other

by-products found in the culture; therefore, they should be used with caution. An example of an

autogenous vaccine is Streptococcus equi developed from horses on farms experiencing out-

breaks of strangles

Multiple-Antigen and Single-Antigen Vaccines

vaccines that contain more than one antigen are referred to as polyvalent. Polyvalent vaccines contain a mixture of different antigens and can be convenient to administer because fewer injections are needed. For a polyvalent vaccine to be approved, the manufacturer must show that each part of the vaccine induces the same level of immunity as does the single-antigen vaccine (referred to as monovalent). advantages: Convenient,· Fewer injections to administer,· Less expensive when giving multiple vaccine antigens. disadvantages: Rate of adverse reactions increases, as the number of antigens increases

other vaccines

Some other possible mechanisms for vaccine production include use of peptides (using chem-

ically synthesized protein fragments that antibodies recognize and bind to), anti-idiotypes (an

antigen-binding region of a given antibody can be antigenic in a different animal causing that ani-

mal to produce antibodies to the original antibody), and synthetic peptides (chemical synthesis of a protein component of a microorganism). Some of these methods have been utilized to a

degree; however, adverse effects and cost have limited their use to date.

9he 21-3 summarizes the type of response stimulated by each vaccine type. Table 21-4 compares

the advantages and disadvantages of various types of vaccines.

Monovalent

advantages: Can select only the desired antigens to administer, · If an animal has had an adverse reaction in the past, they can get different vaccines on different days or not get certain vaccines. disadvantage: Using several monovalent vaccines exposes patients to higher amounts of proteins and possibly adjuvants, · Adverse reactions increase when giving many monovalent vaccines at a time (although this can be decreased by giving them at different times)

stimulates antibody response

· Killed (inactivated)

· Bacterin

· Subunit

. Toxoid

· Attenuated (modified-live if vaccine contains virus;

avirulent-live if vaccine contains bacteria)

· Polynucleotide

stimulates cellular response

· Attenuated (modified-live if vaccine contains virus;

avirulent-live if vaccine contains bacteria)

· Recombinant

· Polynucleotide

inactivated (killed) vaccines, bacterins, subunit vaccines, and toxoids

Advantages

• · No risk of reverting to virulent form (safer for the patient)

• · No risk of vaccine microorganism spreading between animals because microorganism not shed in environment

• · Low abortion risk

• · More stable storage

• . No mixing, which decreases the risk of contamination (does not need reconstitution)

• . Toxoids may require higher levels of biosafety

Disadvantages

• . More likely to cause allergic reactions and postvaccination lumps due to presence of adjuvant

• · Two initial doses needed at least ten days apart

• . Slower onset of immunity

• . Immune response may not be as strong or as long as live, attenuated vaccines

• . Generally stimulates only humoral immunity

• . Tend to be more expensive than live, attenuated vaccines

• . Full protection may not develop until two to three weeks after last immunization

• . Many inactivated vaccines cannot protect against new strains of the pathogen

• · Cannot stimulate an immune response if given orally or intranasally

Live Attenuated Vaccines (modified Live or Avirulent Live)

Advantages

• · Highly immunogenic; therefore, one initial dose is usually sufficient for protection unless maternal antibodies are high (additional boosters may be required)

• · Rapid protection

• · Unlikely to cause allergic reactions or postvaccination lumps

• · Prolonged protection

• · Better at stimulating cell-mediated immunity than killed vaccines

• · Induces both cellular and humoral immunity that mimics natural infection

Disadvantages

• · Could revert to the virulent form but the risk is extremely low to nonexistent

• · Could produce disease in immunosuppressed animals

• · Could produce an excessive immune response

• · Some risk of abortion at initial vaccination

• . Must be handled and mixed with additional care; refrigeration needed

• · Following reconstitution should be administered promptly (within one hour) or discarded

  • · Risk of contamination during mixing because they need to be reconstituted

• · Requires multiplication in the host

type I hypersensitivity (acute anaphlyaxis)

reactions that occur immediately or within a few minutes or hours after exposure to an antigen. Acute swelling typically involving

the head and ears, urticaria (hives), collapse, acute-onset diarrhea,

vomiting, dyspnea, systemic anaphylaxis (shock), death

type IlI hypersensitivity reactions (immune-complex):

intense local inflammation. Cutaneous ischemic vascular disease,

undefined immune-mediated diseases (polyarthritis, glomerulonephritis,

"moon blindness" in horses [may be associated with Leptospira vaccine]

and "blue eye" in dogs [associated with modified-live canine adenovirus-1

vaccines, which are no longer available in the United States])

type IV hypersensitivity (delayed-type hypersensitivity):

 immune diseases such as vaccine-associated sarcoma (sarcomas are tumors of connective-tissue origin) in cats. Associated with decreased cellular immunity and the release of pro-inflammatory cytokines; may be associated with formation of granulomas after vaccination

type Il hypersensitivity reaction (cytotoxic):

autoimmune hemolytic anemia in dogs. immune-mediated thrombocytopenia

Transient injection-site reactions

Visible or palpable lumps, injection-site pain, pruritus, local swelling

Sustained injection-site reactions

Permanent hair loss (generally associated with ischemic vasculitis), discoloration of skin, focal necrosis of skin, granuloma

Transient nonspecific systemic effects

Lethargy, anorexia, fever, regional lymph node enlargement, soreness/discomfort, diarrhea, vomiting

Former 4 Tier Vaccine Label Example

For vaccination of healthy horses four months of age or older as an aid in the prevention of disease caused by Eastern, Western, and Venezuelan encephalomyelitis, and tetanus; as an aid in the prevention of viremia and mortality; as an aid in the reduction of severity of clinical disease caused by West Nile virus; and as an aid in the reduction of respiratory disease caused by equine herpes virus type 1 and equine influenza virus type A2. The duration of immunity against equine influenza is at least 6 months and against West Nile virus is at least 12 months.

Single-Tier Vaccine Label Example

This product has been shown to be effective for the vaccination of healthy horses four months of age or older against Eastern, Western, and Venezuelan encephalomyelitis; tetanus; respiratory diseases caused by equine herpes virus type 1 and equine influenza virus type A2; and West Nile virus. The duration of immunity against equine influenza is at least 6 months, and against West Nile virus is at least 12 months.