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Therapeutics: immune system

ISSN 2398-2977


Podcast: Therapeutics: immune system

Introduction

  • Most immune responses to pathogens or allergens represent a specific reaction to a particular antigen or small number of antigens.
  • Specificity of the immune response means that therapeutic agents that non-specifically potentiate or depress immune system function are likely to have considerable undesirable side effects.
  • Immunity may be acquired by passive or active means.
  • Passive immunity can be provided by:
    • Transfer of maternal antibodies to offspring via the placenta or colostrum.
    • Plasma.
    • Antiserum.
    • Antitoxin. 
  • Active immunity is provided via vaccination.
  • The primary group of therapeutic agents with immunomodulatory effects are vaccines.
Vaccines
  • Particularly effective means of preventing a number of infectious diseases.
  • They expose the animal to a non-pathogenic form, a specific portion of the infectious organism, or inactivated exotoxins produced by a microbe    →   induces a protective humoral (antibody) or cellular (cytotoxic T lymphocytes) immune response.
  • On subsequent exposure to the organism the immune system mounts a rapid and vigorous secondary humoral response that is able to prevent development of clinical infection.
  • Cell-mediated immune response is important in the elimination of virus-infected cells and intracellular bacteria.
  • Depending on the route of administration systemic and/or local (mucosal) immunity may be stimulated.
Vaccine failure
  • Vaccines may fail to protect for a number of reasons which include:
    • Vaccines given to foals may be rendered ineffective by residual maternal immunity.
    • Incorrect storage of vaccine will reduce its immunogenicity.
    • Incorrect timing of inoculations (interference by passive maternal immunity).
    • Vaccine may contain antigen from a different strain of the organism.
    • Partial protection may be overwhelmed by massive pathogen exposure.
    • Individual variations in immune response results in some individuals remaining vulnerable to infection.
    • Concurrent disease during vaccination or subsequent exposure before development of a sufficient immune response.
    • Corticosteroid administration.
Follow the recommendations of vaccine manufacturers and advise clients that no vaccine offers 100% protection. Vaccination protection  Vaccination: adult    Vaccination: broodmare and foal 
  • In some diseases, eg influenza, the benefit of vaccination is that it protects the population (= herd immunity) rather than the individual by reducing the overall frequency of infection.
  • Other vaccines, eg tetanus, are intended to protect individual animals against relatively rare but serious conditions.
  • In general, live vaccines elicit greater protection than killed vaccines.
  • Killed vaccines rely on an adjuvant to increase the immune response.
  • diseases which invoke mucosal surface immunity are best prevented with vaccines utilizing the same part of the immune system, ie local immunization at the mucosal surface.
  • Few such vaccines have been developed for use in the horse.
  • Some modified live viral vaccines can be administered to promote interferon production to create short-term protection when appropriate humoral/cell-mediated immune response cannot be achieved within a short period of time, eg in the face of a viral disease outbreak.
Preparations
  • There are many commercially available vaccines for use in the horse but they cover a relatively narrow range of diseases.
  • There are several types of vaccine:
    • Modified live (attenuated).
    • Vector.
    • DNA.
    • Inactivated (killed).
    • Subunit.
    • Toxoids.
    • Autogenous.
Modified live
  • Vaccine made from live micro-organisms that have been treated in various ways to reduce their pathogenicity.
  • They retain many of the surface antigenic properties of the original microbe and are capable of replication (although this may be restricted) and dissemination, but do not cause disease.
  • They induce humoral (antibody production) and cell-mediated immunity (cytotoxic T lymphocytes).
  • Local and/or systemic immunity can be induced depending on the route of administration, eg intranasal vaccines can protect against respiratory diseases.
  • Variable degree of protection provided depending on the antigen and individual; usually high and of long duration but generally less than following natural infection.
Vector
  • Vaccine produced using a carrier vector (usually a benign mammalian virus, eg canary pox) with poor replication ability but which can express foreign antigens.
  • Induces reasonable immunity against heterolegous antigens.
  • Does not spread beyond vaccinated animals.
  • Example: West Nile Virus   West Nile fever virus  .
DNA
  • Injected recombinant DNA results in direct expression of antigens by the host cell, eliminating the risk of infection, latency or immunity against a vector.
  • Humeral and cellular immunity is induced.
  • Cold storage of these vaccines is not required cf other vaccines.
  • Has been developed for Equine Influenza Virus   Equine influenza vaccine  , but not yet commercially available.
Inactivated (killed)
  • Produced by chemical or heat-treating of live bacteria/viruses.
  • The microbes cannot replicate.
  • Antigen presentation occurs in a restricted manner inducing only humeral immunity and poor cell-mediated immunity.
  • Surface antigens may be modified by the inactivation process.
  • Contain adjuvants to enhance the immune response, eg aluminium hydroxide, aluminium phosphate, liquid paraffin   Liquid paraffin  , alum, carbomer, which can be irritant   →   local reaction and swelling.
  • Strict asepsis must be adopted for administration.
  • Safer than live vaccines in pregnant mares.
  • Two doses are generally required to provide adequate immunity, and annual booster doses are required for continued immunity.
Subunit
  • Inactivated vaccines containing antigenic structures prepared from the microbe, eg surface proteins.
  • Example: some Equine Influenza vaccines   Equine influenza vaccine  .
Toxoids
  • Microbial toxins treated to remove their deleterious properties.
  • Their ability to stimulate antibody formation is not impaired. 
  • Often contain adjuvants.
  • Example: tetanus toxoid   Tetanus toxoid  .
Autogenous
  • Prepared from cultures of material from a lesion on the animal to be vaccinated.
  • Example: papilloma (wart) vaccine   Papilloma virus  .
  • May only be used on the single animal from which the vaccine was produced.
Specific equine vaccines Consult manufacturers' literature for information on efficacy and mode of use. Influenza
  • Respiratory disease   Equine influenza  .
  • The majority of vaccines are killed whole virus which induce a high level of antibodies against virus hemaglutinin   Equine influenza vaccine  .
  • The degree of protection afforded is proportional to the titer of serum antibodies.
  • Give a course of two IM injections 4-6 weeks apart followed by a third dose 5-7 months later and again at 12-18 months after the primary course.
  • Administration of vaccine in alternating limbs increases the number of immunocompetent lymphocyte clones created.
  • Annual boosters are standard, but if viral challenge is high, then give 6 month (bi-annual) booster injections.
  • There are considerable variations between the strains of influenza and little or no protection may be given if a vaccinated horse is exposed to a strain of the virus not included in the vaccine.
  • Most vaccines include strains responsible for the major epizootics in recent years, and the compulsory vaccination of competition horses, has reduced the extent and severity of outbreaks of this disease.
Vaccination of horses in competition against influenza is required by the Jockey Club for all horses that enter racecourses, for whatever reason, and the Federation Equestere Internationale (FEI).
  • Vaccination with tetanus can be combined.
Equine herpesvirus
  • EHV-1 and EHV-4 can cause myeloencephalopathy   CNS: myeloencephalopathy - EHV  , abortion   Abortion: EHV-1  and respiratory disease   Respiratory: EHV infection  .
  • Inactivated (attenuated - live vaccines) are available   Equine herpesvirus vaccine  .
  • Levels of circulating virus neutralizing antibody do not correlate with protection from this disease which suggests that local immunity in the respiratory tract and cellular immunity are important in protection against this viral disease.
Do not administer to horses <5 months old.  Clostridium tetani
  • Horses are very sensitive to the C. tetanitoxin   Tetanus  .
  • The use of formalin treated toxins is particularly effective in protection against the disease   Tetanus toxoid  .
  • Primary course of two doses 4-6 weeks apart (administered in alternating limbs).  
  • Booster vaccines should be given biannually to reduce the likelihood of vaccine reactions (see below).
  • Pregnant mares should receive a booster injection 4-6 weeks before foaling.
  • Tetanus antitoxin   Tetanus antitoxin  (hyperimmune serum) - a prophylaxis/therapeutic approach for acute injuries and for foals of doubtful immune status until primary course of vaccination can be given. Also used to treat tetanus.
 Streptococcus equi
  • Vaccination against S. equihas been used with variable success to protect against strangles   Strangles (Streptococcus equi infection)  using either heat-treated organisms or purified M protein from the cell wall.
  • No vaccines available in the UK.
  • High side-effect rate from older bacterin vaccine.
Adverse reactions
  • Local and systemic reactions to vaccination are possible.
  • Animals should not be vaccinated:
    • Within 4 weeks of receiving corticosteroids or immunosuppressive drugs.
    • If they are unhealthy or febrile.
    • In late pregnancy unless essential.
    • If they are stressed.
Local reactions
  • Edema, swelling and pain may occur transiently at the injection site.
  • Contamination can   →    abscess formation.
  • Coat color change may occur over the site of injection (rare).
  • Adjuvants used in some vaccines may also cause some local reaction.
  • Most local reactions resolve spontaneously.
Systemic reactions
  • Live virus vaccines may cause a transient systemic response in a proportion of horses.
It is essential that horses are healthy at the time of vaccination and not stressed for several days following vaccination with live vaccines.
  • The widespread use and frequent administration of influenza vaccines has inevitably resulted in a number of vaccine reactions although epidemiologic surveys suggest that more severe systemic reactions are only seen in 6 out of every 1000 vaccinated animals and that these are usually the result of the tetanus component of combined vaccines.
  • Signs include:
    • Dependent edema.
    • Pyrexia.
    • Lethargy.
    • Shivering.
    • Restlessness.
  • Treatment with non-steroidal anti-inflammatories is usually indicated   Therapeutics: anti-inflammatory drugs  .
  • There is considerable anecdotal evidence of non-specific post-vaccination reactions   →    poor performance and protracted respiratory signs, including a cough.
  • These may be due to problems with subclinical intercurrent viral disease, however further research is required.
  • Rarely a hypersensitivity reaction may rapidly occur following vaccination:
    • Sweating.
    • Respiratory distress.
    • Salivation.
    • Urticaria.
  • Epinephrine or corticosteroids should be administered promptly.
  • The risk of anaphylaxis increases following repeated doses of heterologous antiserum, tetanus antitoxin.

Plasma products

  • Equine plasma administered to increase circulating antibodies   →   increased resistance to infection.
  • Provides a source of immunoglobulins (mainly IgG) for temporary passive immunity in foals or immunocompromised horses of any age.
  • Non-specific protection afforded by cytokines, lymphokines and other bioactive peptides.
  • May be collected from any healthy horse (preferably local, with appropriate antibodies) or from horses stimulated to produce certain antigen-specific antibodies.
  • 'Immune' supplements are not yet licensed in the UK.
  • Some hyperimmune preparations have been associated with serum sickness and delayed onset hepatic disease.
Products For failure of passive transfer Only 50% of administered IgG persist in the circulation after 24 h, so do not check antibody levels   Blood: biochemistry - gamma globulins  until after this time.
  • Plasma protein half-life = 21 days.
In presence of sepsis or infection, or pre-existing low levels, administered immunoglobulins will be consumed more rapidly. For endotoxemia
  • Plasma administration:
    • Plasma harvested from horses vaccinated with a gram-negative core antigen vaccine   →   production of anti-endotoxin antibodies with wide range of cross-reactivity to gram-negative bacteria.
An adjunct only to anti-inflammatory and other supportive medical care in endotoxemias   Foal: neonatal septicemia syndrome  .
  • Supportive therapy in coagulopathy from liver failure.
For Rhodococcus equi
  • From horses vaccinated with a Rhodococcus equi  Rhodococcus equi  vaccine.
Plasma must be administered before exposure to the organism, therefore administration must be based on knowledge of seasonal pattern of disease.
  • US recommended protocol: 1 l at birth and 1 l at 30-45 days; alternatively vaccinate mare before foaling, give foal 1 l at 25 days and at 45 days   →   immunity lasts to 70 days of age.
  • UK recommended protocol: 1 l to 50 kg foal at birth and 1 l at 30 days.
Must be combined with management strategy for the reduction of R. equiinfections   Rhodococcus equi infection  . For rotavirus infection
  • Plasma produced after vaccination to have a high titer of antibody specific to the H2 strain of rotavirus   Rotavirus  .
  • Can be used prophylactically or when clinical signs appear.
  • 50-100 ml PO TID until signs reduce.
  • Increase dose if signs do not abate after 24-36 h, administer IV if signs severe.

Other agents

Immunosuppressive agents
  • The use of steroids as anti-inflammatory agents is indicated in diseases such as Culicoideshypersensitivity   Insect hypersensitivity  , idiopathic thrombocytopenia   Blood: thrombocytopenia  and immune-mediated vasculitis.
Serum products
  • Products containing antibody to specific antigens that may be given intravenously are available commercially.
Tetanus antitoxin
  • Purified serum from horses that are hyperimmunized with tetanus toxoid   Tetanus toxoid  .
  • This serum contains large amounts of antibody against the tetanus toxin and may be given to horses that may have been exposed to C. tetaniand whose vaccination status is uncertain.
Do not vaccinate at the time of injury, delay until 2 months following tetanus antitoxin administration. Endotoxin specific immunoglobulin Serum products for the treatment of failure of passive transfer  Foal: failure of passive transfer (IgG) 
  • These serum products contain high immunoglobulin levels and may be used when plasma transfusion from the dam or another matched individual is not possible.
  • They are relatively expensive and they should be given to an affected foal if circulating IgG levels are >4 g/l   Immunology: evaluation  .
  • The efficacy of these products may be limited as they may not contain antibodies against the organisms in the foals' regional locality.
Other immunomodulating agents
  • A variety of pharmacologic products containing bacterial cell wall products have been produced, which are purported to enhance the immune system.
  • While there is little evidence that they are effective there is also no evidence that they are not.
  • In the absence of properly controlled clinical trials or a weight of anecdotal evidence from the field, their use cannot be recommended.
  • Anecdotal reports of immunostimulation by levamisole   Levamisole  administered daily PO. No scientific proof. This has been used in some immune-depressed horses, eg post-viral syndrome and Fell Pony syndrome   Immunology: immunodeficiency - Fell pony syndrome  .
Immune-modifying agents

Further Reading

Publications

Refereed papers

Other sources of information

  • Derived from The Veterinary Formulary (1998) 4th edn. Ed: Bishop, Y. British Veterinary Association and Royal Pharmaceutical Society. ISBN 0-85369-412-5.