Vaccines in Small Animals

PRESENTATION

BROCHURE

Vaccines in Small Animals Fernando Fariñas

Vaccines in Small Animals

(editor) María Luisa Palmero Rafael Astorga

Vaccines

Vaccines in Small Animals

in Small Animals Fernando Fariñas

Vaccines in Small Animals

(editor) María Luisa Palmero Rafael Astorga

eBook

available

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Correct vaccination of dogs and cats requires consideration of a broad range of clinical situations and vaccination options, and obliges veterinary surgeons to constantly update their knowledge in order to appropriately deal with the challenges that arise in daily clinical practice.

Using a thoroughly practical approach, this book takes an in-depth look at vaccines and vaccination to provide veterinary professionals with the information they require to address the many doubts and questions that arise in relation to this topic.

TARGET AUDIENCE:

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ESTIMATED

RETAIL RETAILPRICE PRICE ✱ Small animal vets ✱ Veterinary students FORMAT: 17 × 24 cm NUMBER OF PAGES: 192 NUMBER OF IMAGES: 84 BINDING: hardcover ISBN: 978-84-17640-99-6 PUBLISHING DATE: July 2020

00 € €49

Authors FERNANDO FARIÑAS (EDITOR) Expert in the fields of clinical immunology and infectious diseases.

MARÍA LUISA PALMERO Degree in veterinary medicine from the Complutense University of Madrid, Spain. Gattos cat hospital, Madrid.

RAFAEL ASTORGA PhD in veterinary medicine from the University of Murcia, Spain. Full professor of animal health at the University of Córdoba.

KEY FEATURES:

➜ Provides answers to the most frequent doubts about vaccination in cats and dogs. ➜ Includes recommendations about when and how to vaccinate small animals depending on the disease and situation. ➜ Review of the current knowledge on infectious diseases and how they are prevented written by renowned experts in the field.

Presentation of the book Vaccinations form an important part of the health plans we prepare for our pets. In veterinary practice, vaccines are our most effective tool in the preventive medicine arsenal, besides constituting a significant source of income. Vets normally follow the administration guidelines indicated by the manufacturer. However, in recent years questions and even doubts have arisen concerning the duration of the immunity conferred by some vaccines and whether annual revaccinations are required. Contrastingly, other specialists believe that current data do not provide conclusive evidence of the immunity periods claimed by the manufacturers. This places vets in a difficult position when it comes to offering advice to their patients’ owners. Vaccination is not always a harmless procedure and each administration must be accompanied by a risk assessment to determine the vaccine strain’s potential for residual virulence and unwanted side effects. The immunogenicity of a vaccine depends on many factors, not least those specific to each animal, including their age, sex, breed, whether they have any underlying diseases, are being administered immunosuppressants, malnourished, stressed, etc. Another point to consider is that in developed countries, with access to veterinary services, there is a relatively high population of immunosuppressed cats and dogs. A large number of pets receive immunosuppressive therapies for multiple diseases, not to mention the long list of animals that undergo major surgery or suffer from chronic illnesses or “immunodysregulatory” infections. This increases the likelihood of primary vaccination failure, with vaccines that prove ineffective or only confer short-lived immunity. There is a current tendency towards a change in practice and mentality by both veterinary surgeons and pet owners in pursuit of greater, better, and more rational immunisation for our pets.

Vaccines in Small Animals

Immunisation protocols must therefore undergo a change in policy wherein the pet’s vaccination regime forms part of a complete annual health and well-being revision programme. Vaccinating is a clinical activity that should be performed exclusively by vets after a thorough evaluation of each patient’s specific state of health and characteristics, with the ultimate aim being to decide whether or not to vaccinate and, when necessary, to select the most suitable protocol.

The variety of clinical situations, possibilities, and options available for the vaccination of cats and dogs means small animal vets must remain abreast of the latest developments at all times, so they can offer the appropriate solution to any problem that arises in their daily clinical practice. With this in mind, we have decided to publish this book, titled Vaccines in Small Animals, in which the first unit explores the essential knowledge regarding vaccines and vaccinations, followed by two predominantly practical units which will help veterinary clinicians find answers to the many and often significant doubts that arise when practising vaccinology.

hkeita/shutterstock.com

Dr Fernando FariĂąas Guerrero Editor

Authors Fernando Fariñas Guerrero Fernando Fariñas is a recognised expert in the fields of clinical immunology and infectious diseases, and was based outside of Spain for a large part of his professional career.

He is the founder and president of Fundación IO, an organisation dedicated to developing international projects to combat outbreaks of zoonoses and emerging infectious diseases.

He holds an international diploma in tropical medicine and leprology. His work focuses primarily on the study of zoonotic diseases in the fields of infectious pathology and immunoinfectology, vaccinology, immunonutrition, autoimmunity, and immunodeficiencies within the field of clinical immunology.

He is an advisor to various national and international public and private organisations, and a member of specialised study groups including immunotherapy, immunodeficiencies, and vaccinology groups, as well as various working groups focused on vector-borne infectious diseases and zoonoses. He currently coordinates the International Group of Experts on Emerging Infectious Diseases and Zoonoses and the global health group of the One Health Initiative.

He has presented his work at numerous conferences, master’s courses and specialised courses in the fields of clinical immunology, infectious diseases, and vaccinology. He is the author of several books and numerous articles in his field of expertise in both Spanish and international journals.

He currently directs the Institute of Clinical Immunology and Infectious Diseases in Málaga, and serves as president of the Spanish Ynmun Association, which studies immunological and infectious diseases. He has received numerous national and international awards.

Vaccines in Small Animals

Marisa Palmero Colado María Luisa Palmero Colado holds a degree in veterinary medicine from the Complutense University of Madrid, Spain. She is a cofounder of and partner at the Gattos Centro Clínico Felino, a hospital for cats in Madrid. In 2016 she was awarded the title of University Specialist in Endoscopy and Minimally Invasive Surgery by the University of Cáceres at the Jesús Usón Minimally Invasive Surgery Centre. She is certified in feline medicine by the Spanish Small Animal Veterinary Association (AVEPA) (2012) and in 2011 earned her General Practitioner Certificate in Feline Practice from the European School of Veterinary Postgraduate Studies. In 2011 she enrolled in the Feline Internal Medicine course at the Centre for Veterinary Education at the University of Sydney. She is a member of the International Society of Feline Medicine, American Association of Feline Practitioners, Madrid Small Animal Veterinary Asssociation, AVEPA, and the scientific committee of GEMFE (AVEPA’s working group of specialists in feline medicine).

She teaches postgraduate students in feline medicine at CEU-UCH University, Valencia, Spain, as well as in Chile and Argentina.

She is coauthor of the book Enfermedades infecciosas felinas (Feline Infectious Diseases) which was published in 2010, and has authored clinical case reports and original articles in Spanish and international internal medicine and feline medicine journals. She has spoken at conferences in Spain and elsewhere and delivered lectures throughout Spain. Her main areas of interest are internal medicine and diagnostic imaging.

Rafael Astorga Márquez Rafael Jesús Astorga Márquez holds a degree in veterinary medicine from the University of Murcia, Spain. He is currently professor of animal health at the University of Córdoba, where he coordinates year 5 of the Preventive Medicine and Health Policy module of the veterinary medicine degree. He has also served as Vice Dean of Students and University Extension (2006–2010) and academic secretary of the Faculty of Veterinary Medicine (2010–2014). He is a corresponding academic of the Royal Academy of Veterinary Sciences of Eastern Andalusia, a diplomate of the European College of Small Ruminant Health and Management (ECSRHM), and a member of the editorial committee of the journal Producción Animal (Animal Production) since 2013.

He is a member of the AGR-256 research group (Animal Health: Disease Diagnosis and Control) of the University of Córdoba. He has authored numerous publications in technical and scientific journals, as well as JCR-indexed scientific journals, and participated in multiple Spanish and international research projects. His main lines of research are infectious diseases of domestic and wild animals, preventive medicine in companion animals, diagnosis and control of animal salmonellosis, animal health and food safety in Iberian pigs, use of essential oils as an alternative to antimicrobials, mastitis in goats, and farm biosecurity. He has been a member of the Spanish Association of Veterinary Specialists in Laboratory Diagnosis (AVEDILA) since 1997, and served as the organisation’s spokesperson from 2004 to 2009.

Table of contents 1. Unit 1: Basic vaccinology Chapter 1. Immunological aspects of vaccination Chapter 2. Characteristics, types, and composition of vaccines Chapter 3. Immunisation failures Chapter 4. Introduction to vaccine reactions Chapter 5. Frequently asked questions about small animal vaccination

2. Unit 2: Canine vaccination Chapter 6. Parvovirus vaccine failure: myths and realities Chapter 7. Vaccination against leptospirosis Chapter 8. Rabies vaccination Chapter 9. Vaccine protocols Chapter 10. Vaccination in special circumstances Chapter 11. Vaccination against Leishmania

3. Unit 3: Feline vaccination Chapter 12. Vaccination against feline retroviruses Chapter 13. Vaccination against feline infectious peritonitis Chapter 14. Vaccination against calicivirus Chapter 15.Vaccination against herpesviruses Chapter 16. Vaccination against panleukopaenia Chapter 17. Vaccination against feline chlamydiosis Chapter 18. Feline vaccination protocol Chapter 19. Frequently asked questions about feline vaccination

Plaza Antonio Beltrán Martínez, 1 Centro Empresarial El Trovador planta 8, oficina 50002 Zaragoza, España

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+34 976 461 480

Vaccines in Small Animals Fernando FariĂąas

Vaccines in Small Animals

(editor) MarĂ­a Luisa Palmero Rafael Astorga

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01

IMMUNOLOGICAL ASPECTS OF VACCINATION

General introduction to the immune response Throughout evolution, living beings have developed a series of mechanisms and strategies to limit or prevent invasion of the organism by viruses, bacteria, fungi, and parasites.

We live and grow in a microbial world, and defence against these “invaders” has traditionally been considered the main function of the immune system. Similarly, infectious agents have evolved various strategies to invade and settle in our bodies, and to ensure their transmission to other individuals of the same or different species.

Many pathogenic bacteria produce disease by manufacturing millions of toxins in the organism in which they reside (e.g. tetanus). Others, in addition to producing toxins, can invade and penetrate deep into tissues. In many cases, some of these toxins are designed especially to indiscriminately kill the white blood cells or leukocytes, thereby preventing exposure of the infectious agent to the action of these cells. Similarly, many viruses have developed intricate

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mechanisms by which they can modulate and manipulate the immune system. It is not uncommon for viruses to be able to direct and alter the immune response. Their “victims” include phagocytes and lymphocytes of all types. Recall that the main action of retroviruses such as HIV/AIDS, FIV, and FeLV is to “kill” lymphocytes and macrophages, rendering the immune system unable to organise effective defensive responses to the various microbes that populate the external and internal environment, and favouring the development of serious infections.

Many parasites known as “worms” or, more correctly, helminths (e.g. Taenia, Ascaris, Toxocara, Anisakis) have developed other mechanisms that allow them to evade their host’s defences and persist. Among their varied mechanisms of escape is the ability to disguise themselves. These parasites can evade the defensive response by adorning their bodies with proteins belonging to the host organism.

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ImmunologIcal aspects of vaccInatIon

Faced with a staggering diversity of strategies used by infectious agents and other organisms to gain control of the body, animals have had to develop sophisticated mechanisms to control each and every one of these microbes and parasites. The most important and exquisite defensive mechanisms acquired and perfected over millions of years of evolution are without doubt the innate and adaptive immune responses.

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■

Innate and adaptive immune responses Exposure to any antigen will trigger an immune response. This response consists of two phases (Fig. 1):

3

An initial phase that attempts to rapidly contain the pathogen, but is unable to induce a memory response (innate immune response).

A second phase, which consists of a series of highly specific strategies to eliminate the invading agent and create a memory of the encounter (adaptive immune response).

During the early stages of infection, innate immunity is the first line of host defence against invasion by an infectious agent. The innate immune response involves a host of cells (including macrophages, dendritic cells, neutrophils, and NK [natural killer] cells) equipped with receptors to detect potentially dangerous pathogens.

All pathogens carry a distinguishing mark, a series of molecules that are easily recognised by the cells of the immune system.

Components of the immune response

Innate immunity

Physical barriers: ■ Skin ■ Mucosa (mucus)

Chemical barriers: ■ pH of body fluids ■ Antimicrobial peptides (defensins) ■ Proteins (e.g. lysozyme)

Phagocytic cells: ■ Neutrophils ■ Eosinophils ■ Monocytes and macrophages ■ Dendritic cells

Adaptive immunity

Humoral response: ■ Antibodies ■ Cytokines, etc.

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Cellular response: ■ Lymphocytes

Figure 1.

Features of innate and adaptive immunity.

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Vaccines in Small Animals

These markers are called PAMPs (pathogen-associated molecular patterns) and are recognised by immune cells via patternrecognition receptors (PRRs), which include Toll-like receptors (TLRs) (Fig. 2).

Stimulation of any of these receptors by a pathogen leads to production of a number of inflammatory mediators (cytokines).

In contrast to innate immunity, adaptive immunity is specific for a given antigen and generates memory. Therefore, it will protect against potential reinfection by the same pathogen. The coordinated action of CD4+ (T4 or helper) cells, CD8+ (cytotoxic/suppressor) cells, and B effector (plasma) cells gives rise

to the second phase of the specific response to infection.

Depending on the type and number of cytokines formed during the innate response, the final proportions of these molecules will determine the preferential development of an adaptive response based primarily on the following (Fig. 3): ■ A Th1 cellular immune response (with activation of cytotoxic T8 cells and NK cells) ■ A Th2 humoral response (with production of large quantities of quality antibodies) ■ A Th17 response based on the activation of polymorphonuclear neutrophils.

■ A mixed response

ssDNA (virus) TLR3

Profilin

TLR7

ssRNA (virus)

TLR11 TLR8

?

ssRNA (virus) TLR10

TLR9

TLR1 Diacyl-lipopeptides

Cytokines

CpG DNA (bacteria, viruses)

TLR2 TLR5

TLR6 Triacyl-lipopeptides

TLR2

TLR4

Flagellum

Lipopolysaccharides

Figure 2. Different types of Toll-like receptors (TLRs) and the molecules they recognise. TLR activation stimulates the synthesis of cytokines. ss, single-strand; CpG DNA, DNA regions with a high concentration of phosphatelinked cytosine and guanine pairs (involved in the regulation of gene expression).

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5

Th1 and Th17 lymphocytes mainly promote cellular responses against intracellular pathogens, including viruses, numerous bacteria (Mycobacterium, Salmonella, Listeria, etc.), rickettsias, ehrlichias, chlamydias, protozoan parasites (Leishmania, Toxoplasma, Neospora, etc.), and fungi (Histoplasma, Cryptococcus, etc.)

(Table 1).

The immune system uses the Th2 response to defend against extracellular agents, macroscopic parasites (helminths), and toxins. Th2 cells produce many cytokines (IL-4, IL-5, and IL-13) with which they stimulate a humoral immune response, characterised by the production of large quantities of immunoglobulin

by B cells (mainly IgA, IgE, and IgG1). These immunoglobulins in turn mediate the defence against extracellular infectious agents and their toxins. In addition, the Th2 response activates and stimulates the production of eosinophils, which mediate the defence against helminth parasites.

+

Th1 response

+

APC T

IL-2 IL-12

Ag IFN-γ TNF-α

lgG2

Tc

-

B

-

Th2 response

NK cell

-

APC

Tc

T Ag

IL-4 IL-13

NK cell

IL-5

+ B

+

lgG1 lgE lgA

Figure 3. Th1 and Th2 response profile. Ag, antigen; APC, antigen presenting cell; IL, interleukin; IFN-γ, interferon γ; TNF-α, tumour necrosis factor α; T, T cell; NK, natural killer cell; Tc, cytotoxic T cell; B, B cell; Ig, immunoglobulins.

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Vaccines in Small Animals

Table 1. Summary of the characteristics of the adaptive Th1, Th2, and Th17 responses.

Response type

Activated cells

Th1

Cytotoxic T8 and NK cells

Th17

Polymorphonuclear neutrophils

Th2

B cells (synthesis of IgA, IgE, and IgG1) Eosinophils

Pathogens Viruses Numerous bacteria (Mycobacterium, Salmonella, Listeria, etc.)

■ Rickettsias, ehrlichias, and chlamydias ■ Protozoan parasites (Leishmania, Toxoplasma, Neospora, etc.)

■ Fungi (Histoplasma, Cryptococcus, etc.)

■ ■

Extracellular agents Macroscopic parasites (helminths) ■ Toxins ■ ■

Immune response and vaccination

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Terms and definitions It is helpful to review some terms and definitions relating to vaccine immunology: ■ Antigen: a molecule or substance capable of inducing a specific immune response, with the ability to bind to an antibody or to stimulate specific receptors located in the membrane of T cells (T-cell receptor or TCR). Antigens consist of two subclasses: ■ T-independent (TI) antigen: these are generally carbohydrate molecules, e.g. polysaccharides of bacterial capsules or some lipopolysaccharides. They induce the production of IgM by B cells but not IgG, and therefore are unable to induce memory cells.

■ T-dependent antigen (TD): these are normally proteins capable of inducing both humoral and cellular immune responses. Therefore, they can activate the production of IgG antibodies and generate T and B memory cells.

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■

Hapten: a molecule or substance of low molecular weight that is unable to activate an immune response if not associated with another molecule of high molecular weight (carrier).

Primary response: the response generated when the individual is first exposed to an antigen. This response can be both cellular and humoral. In the latter case, the response results in the production of IgM antibodies that have the capacity to neutralise large numbers of antigens, since these are generally tetrameric or pentameric molecules (4 or 5 antibodies joined together by their tails or Fc fractions). This response occurs during the first 5 to 7 days after exposure. As part of this process, T and B memory cells are generated to establish a secondary response should the individual come into subsequent contact with the antigen in question. In most infections, serological detection of this antibody (IgM) is usually indicative of an acute process or recent exposure.

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ImmunologIcal aspects of vaccInatIon

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Secondary response: after primary contact, subsequent exposure of the individual to the same antigen elicits a secondary response. This response is much faster (occurring within a mean of 48 hours), more effective, and involves antibodies (mainly IgG, but also IgA and IgE) with greater affinity for the antigen in question.

In the majority of infections, serological detection of these antibodies is usually indicative of a chronic process or a prior infection (Fig. 4).

When preparing any vaccine it is essential to understand the immunology and immunopathology of the disease in question, although in some cases the specific immune responses involved in resolving the natural infection remain unknown.

The goal of any vaccine is to produce an immune response that is as close as possible to that provoked during natural infection.

Immunisation through vaccination constitutes a “dramatisation”, i.e. an imitation of the immune response induced by the natural infection that triggers mechanisms similar to those activated during the infectious process.

The adaptive immune response, mediated

by B and T cells, is responsible for generating the lasting immunity that follows natural infection or immunisation. After exposure to the antigen, B and T cells proliferate through the

An overview of vaccines Most existing vaccines are used for the prevention or control of acute bacterial or viral infections, although others, such as the leishmaniasis vaccine, prevent the disease rather than the infection.

Second exposure to antigen

Primary exposure to antigen

IgG IgA IgE

IgG

Antibody levels

Antibodysecreting plasma cell IgM

Antibody-secreting plasma cell B cells activated

Secondary response Primary response

5

10

Days after antigen exposure

Long-lived plasma cell (mainly in bone marrow)

Activated B cells

Long-lived plasma cell (mainly in bone marrow)

B cell not stimulated 0

7

Memory B cell

Memory B cell 365

0

5

10

365

Days after antigen exposure

Figure 4. Kinetics of the primary and secondary immune response.

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Vaccines in Small Animals

production of clones, producing antibodies and specific effector cells. After initial antigenic contact, the half-life of the effector lymphocytes is reduced. Therefore, generation of memory cell clones is essential to sustain the specific immune response to infection or immunisation over time. Subsequent antigen exposure triggers a secondary or anamnestic immune response, which is faster and of greater magnitude than the primary response and is often induced with a smaller quantity of inoculum.

The immune response to natural infection or vaccination has typically been evaluated by measuring antibody titres in serum and correlating these titres with different degrees of protection or susceptibility (correlates of protection). This approach is particularly relevant in diseases such as distemper, parvovirus, adenoviral disease, and borreliosis, in which high levels of antibodies correlate very well with the level of protection against infection. However, adequate protection against any infectious agent may require strong cellular immunity, robust humoral immunity, or a combination of both. Infections caused by Bordetella bronchiseptica, coronavirus, or parainfluenza virus can cause significant damage to mucosal surfaces, and effective immunity in these structures is required to ensure a high level of protection. In these diseases, serum antibody concentrations do not correlate with protection. Another characteristic example is Leishmania infantum infection, in which a Th1-type response is required to prevent the dog from developing the disease. Therefore, any vaccine against Leishmania infantum that is based on the production of antibodies alone will be guaranteed to fail. Other diseases in which the presence of antibodies after vaccination is not always correlated with protection include Leptospira, feline calicivirus, and feline herpesvirus.

In general, the concept of evaluating cellular immunity induced by infection with or vaccination against different diseases of dogs and cats has been largely forgotten.

Few studies have quantified this cellular immunity. However, many cases of seronegative animals that are nonetheless protected against disease have been reported over the years. In many, if not all, of these diseases, cellular immunity plays a predominant role in the development of a significant degree of protection.

Therefore, there will be animals that have a low antibody titre and yet are fully protected against the disease thanks to the presence of cellular immunity not measured in diagnostic tests.

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Vaccine design: the nature of the pathogen When designing a vaccine, there are several important factors that must be taken into account to ensure that the vaccine is successful. These include the nature of the pathogen. The optimal candidate pathogens for vaccine development are those that cause acute infections. Those that produce chronic infections are poorer candidates. “Acute” pathogens tend to produce much more powerful and effective immune responses, generating a long-term or even life-long memory response. Therefore, vaccines developed using these types of microorganisms usually induce optimal and long-lasting protective immunity (e.g. canine and feline parvovirus vaccines). Conversely, immune responses to “chronic” pathogens or those that generate persistent infections (e.g. Leishmania, calicivirus, and feline and canine herpesvirus) are typically inadequate or, at best, moderately effective for the elimination or control of infection. Consequently, vaccination against these diseases is usually less successful at stimulating a 100 % effective and protective immune response in the vaccinated individual (partial immunity). In most cases these vaccines will not prevent infection, but will prevent disease to some degree, depending on the type of vaccine.

Pathogens with a low level of antigenic variation are also good candidates for the production of effective vaccines, since the immune response they generate (antibodies, cytotoxic T cells, etc.) will continue to recognise the same pathogen in successive exposures. However, microorganisms that have a high degree of antigenic variation (e.g. feline calicivirus, Leptospira) will have a greater capacity to evade these immune responses, meaning that it is more difficult to develop effective vaccines against them. Other pathogens, such as feline retroviruses, pose additional challenges since they target and alter the functionality of the cells involved in the immune response (CD4+ lymphocytes, macrophages, etc.).

Finally, the best candidate pathogens to produce effective vaccines are those that infect a single species (species restriction), whether canine, feline, human, bovine, etc. These are pathogens that have not developed the capacity to “escape” and cause infection in other species or reservoirs (i.e. ecological niches outside the target species that allow the microorganism to survive when the target species is absent or its population declines).

The ideal pathogen for vaccine development is that which produces an acute infection, has a low level of antigenic variation, and infects a single species.

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Vaccines in Small Animals

Live versus killed vaccines: immunological differences Live or attenuated vaccines There are two main methods used to attenuate an infectious agent: 1. Serial passage: the disease-causing virus is subjected to a series of passages in cell culture or embryonated eggs. Each time the virus is passaged from one embryo/cell culture to another, it improves its ability to replicate in chicken cells but loses its ability to replicate in the cells of the animal to be vaccinated. A virus that will be used in a vaccine can be passaged in embryos or cell culture up to 200 times. This ensures that the attenuated virus loses the ability to correctly replicate in the animal’s cells and can be used in a vaccine.

2. Inactivation: using heat or various chemical agents such as phenol or formaldehyde. This is a less commonly used method.

Attenuated vaccines are more unstable than inactivated vaccines, require maintenance of a cold chain, are more difficult to produce, and are more reactogenic.

It is particularly important to consider the potential of the virus in an attenuated vaccine to revert to a form capable of causing the disease (reversion to virulence).

Mutations that can occur when the vaccine virus replicates in the body can give rise to a more virulent strain. Although this is very unlikely, since the virus’ capacity to replicate is very limited, it must be taken into consideration when developing an attenuated vaccine.

Live or attenuated vaccines can simultaneously induce both cell-type (Th1) and humoral (Th2) immunity, as they produce a low-grade natural infection.

Specifically, unlike inactivated or killed vaccines, the replicative capacity of the vaccine agent means that attenuated vaccines require a lower antigenic load to evoke a response, without the need for adjuvants.

Vaccines containing attenuated viruses stimulate the production of interferons, which can inhibit the antigenic effectiveness of other vaccines with the same characteristics. This issue is circumvented by administering vaccines simultaneously or by separating the administration of vaccines by intervals of at least 4 weeks.

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Killed or inactivated vaccines These vaccines contain the entire inactivated infectious agent or proteins or other small fragments derived from it. Because killed or inactive pathogens cannot replicate, it is impossible for the virus to revert to virulence and consequently cause disease. These vaccines are generally well tolerated, less reactogenic than live vaccines (except bacterins), very safe, and easier to manufacture.

From an immunological point of view, these vaccines are less immunogenic than live vaccines; they induce less robust immune responses and therefore always contain adjuvants, and must be administered in several initial doses followed by several subsequent booster doses to ensure that long-term protection is conferred.

These vaccines are only capable of generating humoral (Th2) responses. They cannot activate cellular responses (Th1) unless specific adjuvants are added (e.g. saponins, CpG DNA, Th1 cytokines), and even in the presence of such adjuvants will never elicit a response comparable to that of an attenuated vaccine.

Differences between live and killed vaccines

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Do not require 2 doses

Require 2 doses

Fewer organisms per dose

Larger amount of antigen

Do not require adjuvants

Require adjuvants

Less chance of causing hypersensitivity reactions

Hypersensitivity reactions are common

Produce interferon

Do not produce interferon

Induce humoral and cellular immunity

Induce humoral immunity

Intramuscular and oral (water) administration

Intramuscular administration

Well adapted to tight vaccination schedules

Difficult to adapt to multiple vaccination schedules

Strong immunity

Weaker immunity

Less stable in storage

More stable in storage

Possible residual virulence

Zero residual virulence

Possible contamination

Low probability of contamination

Affected by antibiotics (bacteria)

Unaffected by antibiotics

Drawbacks

Killed vaccines

Advantages

Drawbacks

Advantages

Live vaccines

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Vaccines in Small Animals

Multivalent vaccines: “immunological doubts” Some veterinary surgeons (fortunately very few) and many owners have doubts relating to vaccination that have no scientific basis whatsoever, and tend to question the use of multivalent vaccines containing 5, 6, or more types of antigen from different agents, suggesting that this may somehow cause saturation or overload of the immune system, leading to an ineffective response to any or all valences or increasing the risk of adverse reactions. These doubts are completely unfounded.

One only needs to consider the immense number of antigens with which each of us (humans and animals) come into contact every day. It is estimated that the immune system is capable of responding simultaneously to at least 1014 antigens.

The idea that the immune system is incapable of responding effectively to 6, 7, or more antigens contained in a given vaccine is therefore unfounded. Furthermore, the risk of adverse reactions is not significantly increased in animals that receive polyvalent versus monovalent vaccines.

What should be taken into account is that when a vaccine contains several components, it may give rise to what is known as “antigenic competition”. This competition can trigger antagonism. It is therefore not recommended to combine vaccines solely for the sake of comfort or ease of administration: it should be made absolutely clear that vaccines should not be mixed freely, as this can induce antagonistic phenomena.

Only multivalent vaccines authorised by official bodies such as the Spanish and European medicines agencies (AEMPS and EMA, respectively) can be used safely. These authorised vaccines have been thoroughly studied and the absence of competition between the antigens contained therein has been proven.

Undoubtedly, furthering our knowledge of the immunological mechanisms that underlie different infectious diseases will have a significant impact on the development of effective vaccines for the prevention of these diseases. A deeper knowledge of these mechanisms of immunity and infection will also help veterinary clinicians to make judicious decisions when selecting vaccines, better predict outcomes, and establish personalised vaccination protocols for pets according to their condition and immunological status.

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VACCINE TYPES, CHARACTERISTICS, AND COMPOSITION

Characteristics of vaccines Vaccines must fulfil the following series of fundamental criteria in order to be administered: 1. Immunogenicity: ability of a vaccine to induce a detectable, long-lasting immune response.

2. Stability: resistance to physical degradation, so that the vaccine can maintain its immunogenicity.

3. Safety: does not induce undesirable adverse reactions (reactogenicity).

4. Efficacy: final outcome when the vaccine is administered to a group of animals under ideal conditions. The efficacy of a vaccine is measured based on the so-called preventable fraction (PF).

A vaccine is considered effective when it achieves a PF of at least 80 %, although some vaccines with a lower PF are made commercially available given their demonstrated safety profile and the absence of more effective vaccines.

5. Effectiveness: final outcome when the vaccine is applied in real conditions or field conditions. Measures the results and the benefits of a population vaccination programme using the vaccine in question.

6. Efficiency: measures the cost–benefit ratio of a given vaccination programme.

% sick or dead control animals – % sick or dead vaccinated animals % sick or dead control animals

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Vaccines in Small Animals

Components of vaccines A vaccine is a multicomponent solution consisting of a principal antigen and an adjuvant; these are the components that will directly stimulate an immune response to the vaccine. Other components of vaccines include: ■ Liquid in suspension: in most cases this is saline or distilled water, which may contain proteins or products derived from the cultures necessary to develop the vaccine (e.g. egg proteins in vaccines attenuated in chicken embryos).

These products are sometimes responsible for allergic reactions to the vaccine.

■ Preservatives: these delay expiration of the vaccine, and include mercury derivatives (thiomersal), phenol, and phenoxyethanol.

■ Stabilisers: these are compounds such as amino acids, sugars, and proteins (albumin, gelatin, etc.) that stabilise all the components of the vaccine. Protein stabilisers can be responsible for the reactogenicity of certain vaccines.

■ Antibiotics: these prevent or reduce bacterial contamination. Antibiotics used include gentamicin, streptomycin, neomycin, and polymyxin B. ■ Adjuvants: adjuvants are one of the most important components of vaccines.

They are substances that enhance and direct the immune response.

Adjuvants Adjuvants enhance the antigenic potency of nonreplicating vaccines. They allow the antigen to persist for longer at the site of injection, achieve maximum activation of antigen-presenting cells (dendritic cells), and induce a local inflammatory response.

Moreover, adjuvants are capable of orienting the immune response to produce antibodies, humoral immunity (Th2), cellular immunity (Th1), or a mixed response (Table 1). For example, aluminium salts are particularly effective in orienting and activating Th2 responses. For this reason they are used in vaccines that require the production of large amounts of antibodies. Saponins such as QA-21 and QS-21 are major inducers of cellular immune responses, and are used in vaccines such as the leishmaniasis vaccine.

The incorporation of proteins or peptides in polymeric constructions (liposomes, micelles, self-assembled proteins) generates larger particles containing a greater density of epitopes (Table 1).

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