Section 3 Types of Vaccines

*Vaccines - The History and Future*

2003;**168**:692-699

Access. 2010

factor-kappaB. American Journal of Respiratory and Critical Care Medicine.

[58] Kubrusly FS, Iourtov D, Leme E, Raw I. Pulmonary surfactant protein A isolation as a by-product of porcine pulmonary surfactant production. Biotechnology and Applied

Biochemistry. 2004;**40**:173-179

[59] de Cássia Dias S, Sakauchi D, Abreu PA, de Lima Netto S, Iourtov D, Raw I, et al. Purification and characterization of aprotinin from porcine lungs. Biotechnology Letters. 2008;**30**:807-812

[60] de Cássia Dias S, dos Santos FL, Sakauchi D, Iourtov D, Raw I, Kubrusly FS. The porcine pulmonary surfactant protein A (pSP-A) immunogenicity evaluation in the murine model. Open

**28**

**31**

**Chapter 3**

**Abstract**

vaccines.

**1. Introduction**

agents and destroy them.

create a vaccine for humans.

vaccine is made.

Vaccine Types

*Xiaoxia Dai, Yongmin Xiong, Na Li and Can Jian*

**Keywords:** vaccine, type, attenuated, inactivated, recombinant

There are several different types of vaccines. Each type is designed to teach your immune system how to fight off certain kinds of germs and the serious diseases they cause. There are four main types of vaccines: live attenuated vaccines; inactivated vaccines; subunit, recombinant, polysaccharide, and conjugate vaccines; and toxoid

Vaccines are biologics that provide active adaptive immunity against specific diseases. Vaccines usually contain drugs that resemble the microorganisms responsible for the disease and are often made from one of the killed or attenuated microorganisms, their toxins, or their surface proteins, introduced by mouth, by injection, or by nasal spray to stimulate the immune system in us and recognize the foreign

There are many success stories in vaccine. The first vaccine, against smallpox, a disease that had killed millions of people over the centuries by British physician Edward Jenner in 1796 [1], was derived from the benign cowpox virus, which provided immunity to small pox. In 1980, following an historic global campaign of surveillance and vaccination, the World Health Assembly declared smallpox eradicated. In the nineteenth and twentieth centuries, scientists following Jenner's model developed new vaccines to fight numerous deadly diseases, including polio, whooping cough, measles, tetanus, yellow fever, typhus, rubella mumps, varicella, and hepatitis B and many others [2]. Rabies was the first virus attenuated in a lab to

The vaccine exposes humans to very small and safe amounts of attenuated or killed viruses and bacteria. When you are exposed to it in later life, the immune system will learn to recognize and attack infections. So you will not get sick, or you may be infected lightly. During the process of immunity development, the body produces antibodies against specific microorganisms and creates defense. The next time the person encounters that microorganism, the antibody prevents him from causing disease or alleviates the severity of the disease, regardless of the way that a

Vaccines are the most cost-effective healthcare interventions known to prevent death and disease. A dollar spent on a childhood vaccination not only helps save a life but greatly reduces spending on future healthcare. According to a new study from the University of North Carolina at Chapel Hill, vaccination efforts made in the world's poorest countries since 2001 will have prevented 20 million deaths and

### **Chapter 3**

### Vaccine Types

*Xiaoxia Dai, Yongmin Xiong, Na Li and Can Jian*

#### **Abstract**

There are several different types of vaccines. Each type is designed to teach your immune system how to fight off certain kinds of germs and the serious diseases they cause. There are four main types of vaccines: live attenuated vaccines; inactivated vaccines; subunit, recombinant, polysaccharide, and conjugate vaccines; and toxoid vaccines.

**Keywords:** vaccine, type, attenuated, inactivated, recombinant

#### **1. Introduction**

Vaccines are biologics that provide active adaptive immunity against specific diseases. Vaccines usually contain drugs that resemble the microorganisms responsible for the disease and are often made from one of the killed or attenuated microorganisms, their toxins, or their surface proteins, introduced by mouth, by injection, or by nasal spray to stimulate the immune system in us and recognize the foreign agents and destroy them.

There are many success stories in vaccine. The first vaccine, against smallpox, a disease that had killed millions of people over the centuries by British physician Edward Jenner in 1796 [1], was derived from the benign cowpox virus, which provided immunity to small pox. In 1980, following an historic global campaign of surveillance and vaccination, the World Health Assembly declared smallpox eradicated. In the nineteenth and twentieth centuries, scientists following Jenner's model developed new vaccines to fight numerous deadly diseases, including polio, whooping cough, measles, tetanus, yellow fever, typhus, rubella mumps, varicella, and hepatitis B and many others [2]. Rabies was the first virus attenuated in a lab to create a vaccine for humans.

The vaccine exposes humans to very small and safe amounts of attenuated or killed viruses and bacteria. When you are exposed to it in later life, the immune system will learn to recognize and attack infections. So you will not get sick, or you may be infected lightly. During the process of immunity development, the body produces antibodies against specific microorganisms and creates defense. The next time the person encounters that microorganism, the antibody prevents him from causing disease or alleviates the severity of the disease, regardless of the way that a vaccine is made.

Vaccines are the most cost-effective healthcare interventions known to prevent death and disease. A dollar spent on a childhood vaccination not only helps save a life but greatly reduces spending on future healthcare. According to a new study from the University of North Carolina at Chapel Hill, vaccination efforts made in the world's poorest countries since 2001 will have prevented 20 million deaths and

#### *Vaccines - The History and Future*

saved \$350 billion in healthcare costs by 2020 [3]. There are still numerous diseases causing globally significant morbidity and mortality, for which no vaccines are available. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, diseases without effective vaccines. This chapter describes the vaccine types now in use and that may lead to the vaccines of the future.

#### **2. Different types of vaccines**

There are several different types of vaccines. Each type is designed to boost your immune system and prevent serious, life-threatening diseases. Four types of vaccines are currently available:


#### **2.1 Live attenuated vaccines**

Live attenuated vaccines contain a version of the living virus that has been weakened so that it does not cause serious disease in people with healthy immune systems. Live attenuated vaccines can be made in several different ways. The most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Viruses are often attenuated by growing them in cells that they do not normally grow in for many generations. With each passage, the virus becomes better at replicating in new cells but loses its ability to replicate in human cells. Eventually, the attenuated virus will be less able to live in human cells and can be used in a vaccine. This method selects mutants that are more suitable for growth under abnormal culture conditions and is therefore less suitable for growth in natural hosts. Therefore, when attenuated viruses are given to a human, they are not able to replicate enough to cause illness like they would naturally but will still provoke an immune response that can protect against future infection. Albert Sabin's oral polio vaccine and measles, rubella, mumps, and varicella vaccines are all achieved by in vitro cell culture passage selection clones. The poliovirus used in the Sabin vaccine is attenuated by the growth of monkey kidney epithelial cells. The measles vaccine contains a strain of rubella virus that grows in duck embryo cells and later grows in human cell lines [4–8]. Another live vaccine that has so far only been used in the military to prevent epidemic pneumonia includes adenoviruses 4 and 7 grown in human diploid cell lines and orally administered for replication in the intestine [9]. Other live vaccines that are attenuated in cell culture passages are attenuated monovalent rotavirus vaccines in Vero cells [10] and Japanese encephalitis virus strain SA14-14-2 [11]. Some viral vaccines are grown in chicken eggs; live attenuated influenza vaccine and yellow fever vaccines are currently produced in embryonated hen's eggs, a method developed in the late 1930s [12, 13].

Live attenuated vaccines have advantages and disadvantages. Live attenuated vaccines are ideal for teaching the immune system against specific viruses because they are closest to natural infections. They often require only a single immunization, eliminating the need for repeated boosters. And these vaccines are relatively easy to create for certain viruses.

**33**

*Vaccine Types*

**Viral:**

• MMR vaccine;

• *Rotavirus* vaccine;

• shingles vaccine;

• *Vaccinia* vaccine.

**2.2 Inactivated vaccines**

• yellow fever vaccine;

*DOI: http://dx.doi.org/10.5772/intechopen.84626*

order to create a weakened version for vaccines. Immunization using this strategy are [14]:

• oral polio vaccine (not used in the USA);

• influenza vaccine (nasal spray) FluMist;

• adenovirus oral vaccine (military); and

• varicella (chickenpox) vaccine;

The Sabine polio vaccine consists of three attenuated poliovirus strains that are orally administered to children in sugar cube or sugar liquid. The attenuated virus colonizes the gut and produces protective immunity against all three virulent poliovirus strains. Unlike most other attenuated vaccines that require a single immunization dose, the Sabin polio vaccine requires a booster because the three attenuated polioviruses in the vaccine interfere with each other's replication in the gut.

The main disadvantage of attenuated vaccines is the possibility they will revert to a virulent form and cause disease. These vaccines cannot be administered to people with weakened immune systems due to cancer, HIV, or other immune system depressing diseases. Attenuated vaccines also may be associated with complications similar to those seen in the natural disease. Live attenuated vaccines usually have to be refrigerated and protected from light. It can be difficult to ship these vaccines overseas and use them in places where there is lack of refrigeration. This technique does not work well for bacteria; therefore there are few live bacterial vaccines. The virus is very simple, but for bacteria, which have thousands of gene, is at least a hundred times larger than a typical virus. This makes bacteria more difficult to control and manipulate than viruses. Currently, scientists are trying to remove key genes from certain bacteria in

Another common method of vaccine production is inactivation of the pathogen by heat or by chemical treatment. This destroys the pathogen's ability to replicate but keeps it "intact" so that the immune system can still recognize it. Maintaining the epitope structure on the epitope antigen during inactivation is critical. Heat inactivation is generally unsatisfactory because it results in extensive denaturation of the protein; therefore, any epitope that is dependent on higher levels of protein structure may change significantly. Chemical inactivation with formaldehyde or formalin has been successful. The Salk polio vaccine is produced by formaldehyde inactivation. Because killed or inactivated pathogens cannot replicate at all, they cannot revert to a more virulent form capable of causing disease (as discussed above with live attenuated vaccines). Attenuated vaccines generally require only one dose to induce long-lasting immunity. However, inactivated vaccine tends to provide a

#### *Vaccine Types DOI: http://dx.doi.org/10.5772/intechopen.84626*

*Vaccines - The History and Future*

**2. Different types of vaccines**

vaccines are currently available:

• live attenuated vaccines;

• inactivated vaccines;

**2.1 Live attenuated vaccines**

• toxoid vaccines.

saved \$350 billion in healthcare costs by 2020 [3]. There are still numerous diseases causing globally significant morbidity and mortality, for which no vaccines are available. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, diseases without effective vaccines. This chapter describes the vaccine

There are several different types of vaccines. Each type is designed to boost your immune system and prevent serious, life-threatening diseases. Four types of

• subunit, recombinant, polysaccharide, and conjugate vaccines; and

embryonated hen's eggs, a method developed in the late 1930s [12, 13].

Live attenuated vaccines have advantages and disadvantages. Live attenuated vaccines are ideal for teaching the immune system against specific viruses because they are closest to natural infections. They often require only a single immunization, eliminating the need for repeated boosters. And these vaccines are relatively

Live attenuated vaccines contain a version of the living virus that has been weakened so that it does not cause serious disease in people with healthy immune systems. Live attenuated vaccines can be made in several different ways. The most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Viruses are often attenuated by growing them in cells that they do not normally grow in for many generations. With each passage, the virus becomes better at replicating in new cells but loses its ability to replicate in human cells. Eventually, the attenuated virus will be less able to live in human cells and can be used in a vaccine. This method selects mutants that are more suitable for growth under abnormal culture conditions and is therefore less suitable for growth in natural hosts. Therefore, when attenuated viruses are given to a human, they are not able to replicate enough to cause illness like they would naturally but will still provoke an immune response that can protect against future infection. Albert Sabin's oral polio vaccine and measles, rubella, mumps, and varicella vaccines are all achieved by in vitro cell culture passage selection clones. The poliovirus used in the Sabin vaccine is attenuated by the growth of monkey kidney epithelial cells. The measles vaccine contains a strain of rubella virus that grows in duck embryo cells and later grows in human cell lines [4–8]. Another live vaccine that has so far only been used in the military to prevent epidemic pneumonia includes adenoviruses 4 and 7 grown in human diploid cell lines and orally administered for replication in the intestine [9]. Other live vaccines that are attenuated in cell culture passages are attenuated monovalent rotavirus vaccines in Vero cells [10] and Japanese encephalitis virus strain SA14-14-2 [11]. Some viral vaccines are grown in chicken eggs; live attenuated influenza vaccine and yellow fever vaccines are currently produced in

types now in use and that may lead to the vaccines of the future.

**32**

easy to create for certain viruses.

The Sabine polio vaccine consists of three attenuated poliovirus strains that are orally administered to children in sugar cube or sugar liquid. The attenuated virus colonizes the gut and produces protective immunity against all three virulent poliovirus strains. Unlike most other attenuated vaccines that require a single immunization dose, the Sabin polio vaccine requires a booster because the three attenuated polioviruses in the vaccine interfere with each other's replication in the gut.

The main disadvantage of attenuated vaccines is the possibility they will revert to a virulent form and cause disease. These vaccines cannot be administered to people with weakened immune systems due to cancer, HIV, or other immune system depressing diseases. Attenuated vaccines also may be associated with complications similar to those seen in the natural disease. Live attenuated vaccines usually have to be refrigerated and protected from light. It can be difficult to ship these vaccines overseas and use them in places where there is lack of refrigeration. This technique does not work well for bacteria; therefore there are few live bacterial vaccines. The virus is very simple, but for bacteria, which have thousands of gene, is at least a hundred times larger than a typical virus. This makes bacteria more difficult to control and manipulate than viruses. Currently, scientists are trying to remove key genes from certain bacteria in order to create a weakened version for vaccines.

Immunization using this strategy are [14]: **Viral:**


#### **2.2 Inactivated vaccines**

Another common method of vaccine production is inactivation of the pathogen by heat or by chemical treatment. This destroys the pathogen's ability to replicate but keeps it "intact" so that the immune system can still recognize it. Maintaining the epitope structure on the epitope antigen during inactivation is critical. Heat inactivation is generally unsatisfactory because it results in extensive denaturation of the protein; therefore, any epitope that is dependent on higher levels of protein structure may change significantly. Chemical inactivation with formaldehyde or formalin has been successful. The Salk polio vaccine is produced by formaldehyde inactivation.

Because killed or inactivated pathogens cannot replicate at all, they cannot revert to a more virulent form capable of causing disease (as discussed above with live attenuated vaccines). Attenuated vaccines generally require only one dose to induce long-lasting immunity. However, inactivated vaccine tends to provide a

shorter length of protection than live vaccines and is more likely to require boosters to create long-term immunity.

A vaccine consisting of orally administered killed cholera bacteria with or without the B subunit of cholera toxin has been developed [15]. Formalin-inactivated whole-cell pertussis vaccine was tested by Madsen [16], and later it was shown to be relatively successful in controlling severe disease [17]. In 1923, Glenny and Hopkins reduced the toxicity of diphtheria toxin by formalin treatment [18]. Ramon has improved this finding and has shown that it is possible to inactivate the toxicity of these molecules while retaining their ability to induce toxin-neutralizing antibodies [19]. In the twentieth century, chemical inactivation was also applied to viruses. Influenza vaccine was the first successful inactivated virus vaccine [20].

Inactivated whole bio vaccines still present certain risks, even if they contain killed pathogens. When formaldehyde failed to kill all viruses in both vaccine batches, serious complications of the first Salk vaccines occurred, which led to a high proportion of polio (poliomyelitis).

Inactivated vaccines are used to protect against:


#### **2.3 Subunit, recombinant, polysaccharide, and conjugate vaccines**

The first vaccine, the smallpox vaccine, consists of live attenuated viruses, but it does not cause disease in human hosts. Many of the vaccines used today, including measles vaccines, yellow fever vaccine, and some influenza vaccines, use live attenuated viruses. Others use inactivated forms of toxins made from killed form of virus, debris of bacteria, or bacteria. The killed virus, bacterial debris, and inactivated toxins will not cause disease but will still cause immune reactions and prevent future infections. However, new techniques are also being developed to make different types of vaccines.

Subunit, recombinant, polysaccharide, and conjugate vaccines are biosynthetic vaccines. Biosynthetic vaccines contain man-made substances that are very similar to pieces of the virus or bacteria. The hepatitis B vaccine is an example.

Since these vaccines use only specific pieces of the germ, they show a very strong immune response, which targets the main part of the germ. It can also be used by almost everyone who needs them, including people with weakened immune system and long-term health problems. Vaccines consisting of specific purified molecules derived from pathogens can avoid some of the risks associated with attenuated or killed organism vaccines.

One limitation of these vaccines is that you may need booster shots to get ongoing protection against diseases.

Subunit vaccines use only a subset of target pathogens to stimulate the immune system's response. This can be done by isolating a specific protein from the pathogen and presenting it separately as an antigen. Acellular pertussis vaccines and influenza vaccines (injected forms) are examples of subunit vaccines.

Another subunit vaccine can be created by genetic engineering. The gene encoding the vaccine protein is inserted into another virus or inserted into a cultured production cell. Vaccine proteins are also produced when the vector virus

**35**

*Vaccine Types*

*DOI: http://dx.doi.org/10.5772/intechopen.84626*

responses and protect future HPV infection.

human vaccine in use for fighting parasites [24].

is propagated. The result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. Many genes encoding surface antigens from viral, bacterial, and protozoal pathogens have been successfully cloned into bacterial, yeast, insect, or mammalian expression systems, and the expressed antigens are used for vaccine development. A hepatitis B vaccine that is approved for use in humans is a recombinant vaccine. The vaccine was developed by cloning the hepatitis B virus surface antigen (HBsAg) gene and expressing it in yeast cells. Recombinant yeast cells proliferate in large fermenters, and HBsAg accumulates in cells. At the end of the fermentation, recombinant HBsAg are harvested by disrupting yeast cells, which is then purified by biochemical techniques. This recombinant hepatitis B vaccine has

been shown to induce the production of protective antibodies [21, 22].

Human papillomavirus (HPV) vaccine is another vaccine made using genetic engineering. Two types of HPV vaccine are available, Gardasil (marketed by Merck and protecting against types 6, 11, 16, and 18 of the human papillomavirus) and Cervarix (marketed by GlaxoSmithKline and protecting against types 16 and 18 only). Both are made in the same way: for each strain, a single viral protein was isolated. When these proteins are expressed, viruslike particles (VLPs) are produced. These VLPs contain no genetic material that causes disease but promote immune

Recombinant vector vaccines use attenuated viruses (or bacterial strains) as vectors. A gene encoding a major antigen of a particularly virulent pathogen can be introduced into an attenuated virus or bacterium. The attenuated organism acts as a vector that replicates and expresses the gene product of the pathogen in the host. Baculovirus which is a virus that infects only insects can be used as a vector, and genes for specific immunogenic surface proteins of influenza virus can be inserted. Once the modified virus is introduced into humans, the immunogen is expressed and displayed, producing an immune response against the immunogen and producing an immune response to the immunogen from which it is derived. In addition to insect viruses, human adenoviruses have been identified as potential carriers for recombinant vaccines, particularly against diseases such as AIDS. *Vaccinia virus*, the attenuated vaccine used to eradicate smallpox, was the first used in live recombinant vaccine approaches [23]. This large, complex virus, with a genome of about 200 genes, can be designed to carry dozens of foreign genes without compromising their ability to infect host cells and replicate. Experimental recombinant vaccinia strains have been designed to provide protection against influenza, rabies, and hepatitis B and other diseases. DNA vaccines consist of plasmid DNA encoding antigenic proteins which are injected directly into the muscle of the recipient. The DNA itself inserts into the individual's cells, which then produce the antigen from the infectious agent. DNA vaccines have advantages over many existing vaccines. For example, the encoded protein is a native form of the host and has no denaturation or alteration. Therefore, the immune response is identical to the antigen expressed by the pathogen. The handling and storage of plasmid DNA do not require refrigeration, a feature that greatly reduces the cost and complexity of delivery. At present, there are human trials underway with several different DNA vaccines, including those for malaria, AIDS, influenza, and herpesvirus. Researchers hope that DNA vaccines can produce immunity against parasitic diseases such as malaria; however, there is currently no

Conjugate vaccines are somewhat similar to recombinant vaccines: they are prepared using a combination of two different components. The conjugate vaccine was prepared using fragments from the coats of bacteria. These coatings are chemically linked to a carrier protein which is used as a vaccine. Conjugate vaccines are used to produce a more powerful co-immune response: in general, the presented

#### *Vaccine Types DOI: http://dx.doi.org/10.5772/intechopen.84626*

*Vaccines - The History and Future*

to create long-term immunity.

high proportion of polio (poliomyelitis).

• hepatitis A;

• rabies.

• flu (shot only);

ent types of vaccines.

killed organism vaccines.

ing protection against diseases.

• polio (shot only); and

Inactivated vaccines are used to protect against:

shorter length of protection than live vaccines and is more likely to require boosters

Inactivated whole bio vaccines still present certain risks, even if they contain killed pathogens. When formaldehyde failed to kill all viruses in both vaccine batches, serious complications of the first Salk vaccines occurred, which led to a

Influenza vaccine was the first successful inactivated virus vaccine [20].

**2.3 Subunit, recombinant, polysaccharide, and conjugate vaccines**

to pieces of the virus or bacteria. The hepatitis B vaccine is an example.

enza vaccines (injected forms) are examples of subunit vaccines.

The first vaccine, the smallpox vaccine, consists of live attenuated viruses, but it does not cause disease in human hosts. Many of the vaccines used today, including measles vaccines, yellow fever vaccine, and some influenza vaccines, use live attenuated viruses. Others use inactivated forms of toxins made from killed form of virus, debris of bacteria, or bacteria. The killed virus, bacterial debris, and inactivated toxins will not cause disease but will still cause immune reactions and prevent future infections. However, new techniques are also being developed to make differ-

Subunit, recombinant, polysaccharide, and conjugate vaccines are biosynthetic vaccines. Biosynthetic vaccines contain man-made substances that are very similar

Since these vaccines use only specific pieces of the germ, they show a very strong immune response, which targets the main part of the germ. It can also be used by almost everyone who needs them, including people with weakened immune system and long-term health problems. Vaccines consisting of specific purified molecules derived from pathogens can avoid some of the risks associated with attenuated or

One limitation of these vaccines is that you may need booster shots to get ongo-

Subunit vaccines use only a subset of target pathogens to stimulate the immune system's response. This can be done by isolating a specific protein from the pathogen and presenting it separately as an antigen. Acellular pertussis vaccines and influ-

Another subunit vaccine can be created by genetic engineering. The gene encoding the vaccine protein is inserted into another virus or inserted into a cultured production cell. Vaccine proteins are also produced when the vector virus

A vaccine consisting of orally administered killed cholera bacteria with or without the B subunit of cholera toxin has been developed [15]. Formalin-inactivated whole-cell pertussis vaccine was tested by Madsen [16], and later it was shown to be relatively successful in controlling severe disease [17]. In 1923, Glenny and Hopkins reduced the toxicity of diphtheria toxin by formalin treatment [18]. Ramon has improved this finding and has shown that it is possible to inactivate the toxicity of these molecules while retaining their ability to induce toxin-neutralizing antibodies [19]. In the twentieth century, chemical inactivation was also applied to viruses.

**34**

is propagated. The result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. Many genes encoding surface antigens from viral, bacterial, and protozoal pathogens have been successfully cloned into bacterial, yeast, insect, or mammalian expression systems, and the expressed antigens are used for vaccine development. A hepatitis B vaccine that is approved for use in humans is a recombinant vaccine. The vaccine was developed by cloning the hepatitis B virus surface antigen (HBsAg) gene and expressing it in yeast cells. Recombinant yeast cells proliferate in large fermenters, and HBsAg accumulates in cells. At the end of the fermentation, recombinant HBsAg are harvested by disrupting yeast cells, which is then purified by biochemical techniques. This recombinant hepatitis B vaccine has been shown to induce the production of protective antibodies [21, 22].

Human papillomavirus (HPV) vaccine is another vaccine made using genetic engineering. Two types of HPV vaccine are available, Gardasil (marketed by Merck and protecting against types 6, 11, 16, and 18 of the human papillomavirus) and Cervarix (marketed by GlaxoSmithKline and protecting against types 16 and 18 only). Both are made in the same way: for each strain, a single viral protein was isolated. When these proteins are expressed, viruslike particles (VLPs) are produced. These VLPs contain no genetic material that causes disease but promote immune responses and protect future HPV infection.

Recombinant vector vaccines use attenuated viruses (or bacterial strains) as vectors. A gene encoding a major antigen of a particularly virulent pathogen can be introduced into an attenuated virus or bacterium. The attenuated organism acts as a vector that replicates and expresses the gene product of the pathogen in the host.

Baculovirus which is a virus that infects only insects can be used as a vector, and genes for specific immunogenic surface proteins of influenza virus can be inserted. Once the modified virus is introduced into humans, the immunogen is expressed and displayed, producing an immune response against the immunogen and producing an immune response to the immunogen from which it is derived. In addition to insect viruses, human adenoviruses have been identified as potential carriers for recombinant vaccines, particularly against diseases such as AIDS. *Vaccinia virus*, the attenuated vaccine used to eradicate smallpox, was the first used in live recombinant vaccine approaches [23]. This large, complex virus, with a genome of about 200 genes, can be designed to carry dozens of foreign genes without compromising their ability to infect host cells and replicate. Experimental recombinant vaccinia strains have been designed to provide protection against influenza, rabies, and hepatitis B and other diseases.

DNA vaccines consist of plasmid DNA encoding antigenic proteins which are injected directly into the muscle of the recipient. The DNA itself inserts into the individual's cells, which then produce the antigen from the infectious agent. DNA vaccines have advantages over many existing vaccines. For example, the encoded protein is a native form of the host and has no denaturation or alteration. Therefore, the immune response is identical to the antigen expressed by the pathogen. The handling and storage of plasmid DNA do not require refrigeration, a feature that greatly reduces the cost and complexity of delivery. At present, there are human trials underway with several different DNA vaccines, including those for malaria, AIDS, influenza, and herpesvirus. Researchers hope that DNA vaccines can produce immunity against parasitic diseases such as malaria; however, there is currently no human vaccine in use for fighting parasites [24].

Conjugate vaccines are somewhat similar to recombinant vaccines: they are prepared using a combination of two different components. The conjugate vaccine was prepared using fragments from the coats of bacteria. These coatings are chemically linked to a carrier protein which is used as a vaccine. Conjugate vaccines are used to produce a more powerful co-immune response: in general, the presented "fragments" of the bacteria do not themselves produce a strong immune response, while the carrier protein produces a strong immune response. This fragment of bacterium does not cause disease, but when combined with carrier proteins, it can produce immunity against future infections. The vaccines currently in use for children against pneumococcal bacterial infections are made using this technique.

These vaccines are used to protect against:


#### **2.4 Toxoid vaccines**

Toxoid vaccines are made from selected toxins that have been sufficiently attenuated and are able to induce a humoral immune response. These toxins produce many of the symptoms of the disease. For example, diphtheria and tetanus vaccines can be prepared by purifying bacterial toxins and then inactivating toxin with formaldehyde to form a toxoid. Inoculating with a toxoid induces an anti-toxoid antibody that is also capable of binding toxins and neutralizing their effects.

Toxoid vaccines tend not to have a duration of immunity comparable to attenuated viral vaccines; therefore, toxid vaccines, like some other types of vaccines, may need booster shots to get ongoing protection against diseases. Revaccination (booster) may be required multiple times in a single year depending on individual patient risk factors.

Toxoid vaccines are used to protect against:


#### **3. Summary**

There are still the needs for vaccines against other diseases. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, among which there are no effective disease vaccine. The road to successful development of vaccines that can be approved for human use, reasonably manufactured cost, and effective delivery to high-risk groups is expensive, long, and tedious.

**37**

**Author details**

*Vaccine Types*

**Acknowledgements**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.84626*

(Grant Nos. 81673117 and 81573140).

We have no conflict of interest.

This work was supported by the National Natural Scientific Foundation of China

provided the original work is properly cited.

Shaanxi, People's Republic of China

Xiaoxia Dai\*, Yongmin Xiong, Na Li and Can Jian

\*Address all correspondence to: xxiadai@mail.xjtu.edu.cn

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an,

Researchers continue to develop new vaccine types and improve current approaches.

### **Acknowledgements**

*Vaccines - The History and Future*

• hepatitis B;

• shingles.

**2.4 Toxoid vaccines**

neutralizing their effects.

• diphtheria; and

• tetanus.

**3. Summary**

approaches.

Toxoid vaccines are used to protect against:

delivery to high-risk groups is expensive, long, and tedious.

These vaccines are used to protect against:

• human papillomavirus (HPV);

• pneumococcal disease;

• meningococcal disease; and

• *Haemophilus influenzae* type b (Hib) disease;

• whooping cough (part of the DTaP combined vaccine);

"fragments" of the bacteria do not themselves produce a strong immune response, while the carrier protein produces a strong immune response. This fragment of bacterium does not cause disease, but when combined with carrier proteins, it can produce immunity against future infections. The vaccines currently in use for children against pneumococcal bacterial infections are made using this technique.

Toxoid vaccines are made from selected toxins that have been sufficiently attenuated and are able to induce a humoral immune response. These toxins produce many of the symptoms of the disease. For example, diphtheria and tetanus vaccines can be prepared by purifying bacterial toxins and then inactivating toxin with formaldehyde to form a toxoid. Inoculating with a toxoid induces an anti-toxoid antibody that is also capable of binding toxins and

Toxoid vaccines tend not to have a duration of immunity comparable to attenuated viral vaccines; therefore, toxid vaccines, like some other types of vaccines, may need booster shots to get ongoing protection against diseases. Revaccination (booster) may be required multiple times in a single year depending on individual patient risk factors.

There are still the needs for vaccines against other diseases. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, among which there are no effective disease vaccine. The road to successful development of vaccines that can be approved for human use, reasonably manufactured cost, and effective

Researchers continue to develop new vaccine types and improve current

**36**

This work was supported by the National Natural Scientific Foundation of China (Grant Nos. 81673117 and 81573140).

### **Conflict of interest**

We have no conflict of interest.

### **Author details**

Xiaoxia Dai\*, Yongmin Xiong, Na Li and Can Jian School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China

\*Address all correspondence to: xxiadai@mail.xjtu.edu.cn

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Behbehani AM. The smallpox story: Life and death of an old disease. Microbiological Reviews. 1983;**47**(4):455-509

[2] Plotkin S. History of vaccination. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(34):12283-12287

[3] Ozawa S, Clark S, Portnoy A, Grewal S, Stack ML, Sinha A, et al. Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020. Bulletin of the World Health Organization. 2017;**95**(9):629

[4] Sabin AB, Hennessen WA, Winsser J. Studies on variants of poliomyelitis virus—I: Experimental segregation and properties of avirulent variants of three immunologic types. The Journal of Experimental Medicine. 1954;**99**(6):551-576

[5] Katz SL et al. Studies on an attenuated measles-virus vaccine—VIII: General summary and evaluation of the results of vaccination. American Journal of Diseases of Children. 1960;**100**:942-946

[6] Hilleman MR, Buynak EB, Weibel RE, Stokes J Jr. Live, attenuated mumpsvirus vaccine. The New England Journal of Medicine. 1968;**278**(5):227-232

[7] Plotkin SA, Farquhar JD, Katz M, Buser F. Attenuation of RA 27-3 rubella virus in WI-38 human diploid cells. American Journal of Diseases of Children. 1969;**118**(2):178-185

[8] Takahashi M, Okuno Y, Otsuka T, Osame J, Takamizawa A. Development of a live attenuated varicella vaccine. Biken Journal. 1975;**18**(1):25-33

[9] Top FH Jr, Buescher EL, Bancroft WH, Russell PK. Immunization with live types 7 and 4 adenovirus

vaccines—II: Antibody response and protective effect against acute respiratory disease due to adenovirus type 7. The Journal of Infectious Diseases. 1971;**124**(2):155-160

[10] Bernstein DI et al. Safety and immunogenicity of live, attenuated human rotavirus vaccine 89-12. Vaccine. 1998;**16**(4):381-387

[11] Trent DW, Minor P, Jivapaisarnpong T, Shin J, WHO Working Group on the Quality, Safety and Efficacy of Japanese Encephalitis Vaccines Live Attenuated for Human Use. WHO working group on the quality, safety and efficacy of Japanese encephalitis vaccines (live attenuated) for human use, Bangkok, Thailand, 21-23 February, 2012. Biologicals. 2013;**41**(6):450-457

[12] Frierson JG. The yellow fever vaccine: A history. The Yale Journal of Biology and Medicine. 2010;**83**:77-85

[13] WHO. Recommendations to assure the quality, safety and efficacy of live attenuated yellow fever vaccines. Technical Report Series 978 Annex 5; 2010. pp. 241-314

[14] Minor PD. Live attenuated vaccines: Historical successes and current challenges. Virology. 2015;**479**-**480**:379-392

[15] Holmgren J et al. An oral B subunitwhole cell vaccine against cholera: From concept to successful field trial. Advances in Experimental Medicine and Biology. 1987;**216B**:1649-1660

[16] Madsen C. Vaccination against whooping cough. Journal of the American Medical Association. 1933;**101**:187-188

[17] Sauer LW. Whooping cough: Prevention and treatment. The Medical Clinics of North America. 1946;**30**:45-59

**39**

*Vaccine Types*

1923;**4**:283-288

1936;**33**:604-606

2010;**28**:589-590

*DOI: http://dx.doi.org/10.5772/intechopen.84626*

[18] Glenny AT, Hopkins BE. Diphtheria toxoid as an immunizing agent. British Journal of Experimental Pathology.

[19] Ramon C. Sur le pouvoir floculant et sur les propriétés immunisantes d'une toxine diphthérique rendu anatoxique. Comptes Rendus de l'Académie des Sciences. 1923;**177**:1338-1340

[20] Francis T Jr, Magil TP. Vaccination of human subjects with virus of human influenza. Proceedings of the Society for Experimental Biology and Medicine.

[21] World Health Organization. Hepatitis B vaccines: WHO position paper—recommendations. Vaccine.

[22] World Health Organization. Global health sector strategy on Viral hepatitis 2016-2021. Towards ending viral hepatitis. WHO/HIV/2016.06

[23] Plotkin S, Mortimer E. Vaccines. New York: Harper Perennial; 1988

[24] Jaurigue JA, Seeberger PH. Parasite carbohydrate vaccines. Front Cell Infect

Microbiology. 2017;**7**:248

*Vaccine Types DOI: http://dx.doi.org/10.5772/intechopen.84626*

[18] Glenny AT, Hopkins BE. Diphtheria toxoid as an immunizing agent. British Journal of Experimental Pathology. 1923;**4**:283-288

[19] Ramon C. Sur le pouvoir floculant et sur les propriétés immunisantes d'une toxine diphthérique rendu anatoxique. Comptes Rendus de l'Académie des Sciences. 1923;**177**:1338-1340

[20] Francis T Jr, Magil TP. Vaccination of human subjects with virus of human influenza. Proceedings of the Society for Experimental Biology and Medicine. 1936;**33**:604-606

[21] World Health Organization. Hepatitis B vaccines: WHO position paper—recommendations. Vaccine. 2010;**28**:589-590

[22] World Health Organization. Global health sector strategy on Viral hepatitis 2016-2021. Towards ending viral hepatitis. WHO/HIV/2016.06

[23] Plotkin S, Mortimer E. Vaccines. New York: Harper Perennial; 1988

[24] Jaurigue JA, Seeberger PH. Parasite carbohydrate vaccines. Front Cell Infect Microbiology. 2017;**7**:248

**38**

*Vaccines - The History and Future*

[1] Behbehani AM. The smallpox story: Life and death of an old disease. Microbiological Reviews. vaccines—II: Antibody response and protective effect against acute respiratory disease due to adenovirus type 7. The Journal of Infectious Diseases. 1971;**124**(2):155-160

[10] Bernstein DI et al. Safety and immunogenicity of live, attenuated human rotavirus vaccine 89-12. Vaccine.

[12] Frierson JG. The yellow fever vaccine: A history. The Yale Journal of Biology and Medicine. 2010;**83**:77-85

[14] Minor PD. Live attenuated vaccines: Historical successes and current challenges. Virology.

Biology. 1987;**216B**:1649-1660

[16] Madsen C. Vaccination against whooping cough. Journal of the American Medical Association.

[17] Sauer LW. Whooping cough: Prevention and treatment. The Medical Clinics of North America. 1946;**30**:45-59

2010. pp. 241-314

2015;**479**-**480**:379-392

1933;**101**:187-188

[13] WHO. Recommendations to assure the quality, safety and efficacy of live attenuated yellow fever vaccines. Technical Report Series 978 Annex 5;

[15] Holmgren J et al. An oral B subunitwhole cell vaccine against cholera: From concept to successful field trial. Advances in Experimental Medicine and

[11] Trent DW, Minor P, Jivapaisarnpong T, Shin J, WHO Working Group on the Quality, Safety and Efficacy of Japanese Encephalitis Vaccines Live Attenuated for Human Use. WHO working group on the quality, safety and efficacy of Japanese encephalitis vaccines (live attenuated) for human use, Bangkok, Thailand, 21-23 February, 2012. Biologicals. 2013;**41**(6):450-457

1998;**16**(4):381-387

[2] Plotkin S. History of vaccination. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(34):12283-12287

[3] Ozawa S, Clark S, Portnoy A, Grewal S, Stack ML, Sinha A, et al. Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020. Bulletin of the World Health

[4] Sabin AB, Hennessen WA, Winsser J. Studies on variants of poliomyelitis virus—I: Experimental segregation and properties of avirulent variants of three immunologic types. The Journal of Experimental Medicine.

Organization. 2017;**95**(9):629

[5] Katz SL et al. Studies on an

attenuated measles-virus vaccine—VIII: General summary and evaluation of the results of vaccination. American Journal of Diseases of Children.

[6] Hilleman MR, Buynak EB, Weibel RE, Stokes J Jr. Live, attenuated mumpsvirus vaccine. The New England Journal of Medicine. 1968;**278**(5):227-232

[7] Plotkin SA, Farquhar JD, Katz M, Buser F. Attenuation of RA 27-3 rubella virus in WI-38 human diploid cells. American Journal of Diseases of

Children. 1969;**118**(2):178-185

[8] Takahashi M, Okuno Y, Otsuka T, Osame J, Takamizawa A. Development of a live attenuated varicella vaccine. Biken Journal. 1975;**18**(1):25-33

[9] Top FH Jr, Buescher EL, Bancroft WH, Russell PK. Immunization with live types 7 and 4 adenovirus

1954;**99**(6):551-576

1960;**100**:942-946

**References**

1983;**47**(4):455-509

**41**

Section 4

Targeting Zoonotic

Diseases via Vaccination

Section 4

## Targeting Zoonotic Diseases via Vaccination

**43**

**2. Hantavirus**

**Chapter 4**

**Abstract**

**1. Introduction**

Vaccines Targeted to Zoonotic

Viral Infections in the Wildlife:

Currently, emerging viruses such as arboviruses, flaviviruses, filovirus, and *orthohepeviruses* are important agents of emerging zoonoses in public health, because their cycles are maintained in the nature or wildlife, involving hematophagous arthropod vectors and a wide range of vertebrate hosts as the bats. Development of blocking-transmission vaccines against these emerging viruses in wildlife will allow disease control at the veterinary field, preventing emerging human viral infections.

Emerging and/or re-emerging zoonotic viral infections affect significantly the human health in many geographic areas of the world, highlighting their potential to spread from animal reservoirs and their ability to evolve their virulence properties. While the transmission of viruses from wild animal species to human is intermittent or rare, vaccines against zoonotic viral infections should be focused in wildlife

In this chapter, we will focus on the vaccination in wildlife reservoirs, such as bats, rodents, boars, and carnivores, which play an important role in transmission of three emerging zoonotic viruses, rabies virus (RABV), hantavirus, and hepatitis

We discuss the main challenges for efficacy improvement of vaccines, considering the diversity of viral *quasispecies* and antigenic and immunogenicity variations, as well as the biosafety and logistic problems associated to the delivery systems in the wildlife scenery. Finally, other emerging lethal viruses and the current approach

*Hantaviruses* belong to family *Bunyaviridae*; they are enveloped viruses and have a negative-sense RNA organized in three segments denoted as small (S), medium (M),

Potentials, Limitations, and

*Salas-Rojas Mónica, Gálvez-Romero Guillermo* 

Future Directions

*and Pompa-Mera Ericka Nelly*

**Keywords:** vaccines, HEV, hantavirus, RABV, wildlife

reservoirs in order to prevent human disease.

E virus (HEV), to domestic species and humans.

to the development of vaccines will be discussed.

#### **Chapter 4**

## Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future Directions

*Salas-Rojas Mónica, Gálvez-Romero Guillermo and Pompa-Mera Ericka Nelly*

#### **Abstract**

Currently, emerging viruses such as arboviruses, flaviviruses, filovirus, and *orthohepeviruses* are important agents of emerging zoonoses in public health, because their cycles are maintained in the nature or wildlife, involving hematophagous arthropod vectors and a wide range of vertebrate hosts as the bats. Development of blocking-transmission vaccines against these emerging viruses in wildlife will allow disease control at the veterinary field, preventing emerging human viral infections.

**Keywords:** vaccines, HEV, hantavirus, RABV, wildlife

#### **1. Introduction**

Emerging and/or re-emerging zoonotic viral infections affect significantly the human health in many geographic areas of the world, highlighting their potential to spread from animal reservoirs and their ability to evolve their virulence properties. While the transmission of viruses from wild animal species to human is intermittent or rare, vaccines against zoonotic viral infections should be focused in wildlife reservoirs in order to prevent human disease.

In this chapter, we will focus on the vaccination in wildlife reservoirs, such as bats, rodents, boars, and carnivores, which play an important role in transmission of three emerging zoonotic viruses, rabies virus (RABV), hantavirus, and hepatitis E virus (HEV), to domestic species and humans.

We discuss the main challenges for efficacy improvement of vaccines, considering the diversity of viral *quasispecies* and antigenic and immunogenicity variations, as well as the biosafety and logistic problems associated to the delivery systems in the wildlife scenery. Finally, other emerging lethal viruses and the current approach to the development of vaccines will be discussed.

#### **2. Hantavirus**

*Hantaviruses* belong to family *Bunyaviridae*; they are enveloped viruses and have a negative-sense RNA organized in three segments denoted as small (S), medium (M), and large (L) [1, 2]. Unlike the other genera in the family, the hantaviruses are not transmitted by arthropods; their hosts are rodents and insectivores, and there is often an association of a type of virus with a host species [2]. In addition, new hantaviruses have been described in moles and shrews, as well as in bats, which increases the host range [3, 4]. Hantaviruses are maintained in rodent populations asymptomatic. Human infections are accidental (spillover), since for epidemiology and/or virus transmission cycle, the latter are a dead end (except for the case of Andes virus, where humanhuman transmission has been reported) [1, 5]. Transmissions among organisms occur by aerosol exposure, either by urine, feces, or saliva of infected animals, mainly [1].

In rodents, hantavirus infection has an acute phase (peak viremia) during first 2–3 weeks, with virus replication in target tissues and finally a persistent infection [1]. In humans, hantavirus infection can produce two presentations of the disease, depending on the type of virus with which it is infected: hemorrhagic fever with renal syndrome (HFRS) that occurs in Europe and Asia (Old World) mainly and the syndrome cardiopulmonary by hantavirus (HCPS) reported in the Americas (New World) [6]. It is important to note that HFRS can be caused by different viruses, the most common being Puumala and Dobrava in Europe and Hantaan and Seoul in Asia, while for the HCPS, the most common and lethal are *Sin Nombre* in North America and Andes in South America [7].

#### **3. Vaccines against hantavirus**

Currently, vaccine for humans approved by the FDA or any other institution for use in the USA or Europe is not available. An inactivated virus vaccine produced in mouse brain or in cell culture infected with Hantaan virus (HFRS vaccine) is applied in China and Korea. However, this vaccine may not be as effective against the other viruses that produce HFRS in Europe (Puumala and Dobrava) and not for those who produce HCPS (Sin Nombre and Andes) [7].

Considering the variety of hantaviruses and hosts, as well as the fact that there is no authorized or commercialized vaccine for human use that protects against all types of hantavirus, the development of a vaccine that can be applied to the natural reservoir (in this case rodents) is an option that should be considered.

When talking about vaccinating wildlife, the best option is the use of baits, which contain antigenic vaccine material, with stability under different environmental conditions. Since the capture and direct application of a vaccine would be unfeasible and the dispersion by a liquid or air (aerosol) constitutes a not selective administration, which might reach undesirable species and risk the risk of adverse effect, dispersion of the vaccine in species that had not been in contact naturally (in the case of attenuated vaccines) may not reach the desired species.

The viral target to which the vaccines are directed could be the Gn and Gc glycoproteins, which interact with the cellular receptor (integrins) for the entry of the virus into the cell [8]. We must consider the variability among the hantaviruses that can infect humans, since, as mentioned above, the vaccine applied in China and Korea runs the risk that, if it is not well designed, different vaccines against the hantavirus should be applied according to the region. Another point to consider in the design of this vaccine is the host variability that hantaviruses have as a group [6].

Mendoza et al. [9] described several characteristics desirable in the vaccine baits, such as having palatable baits for different species and stability of the vaccine in different environmental conditions among others. Development vaccine for animal use is faster in the process approval for commercial use. In this regard, the cost-benefit ratio is better, since the cost of production and distribution of a vaccine for veterinary use is lower, among other things [9].

**45**

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future…*

The idea of One Health program, recently developed and adopted (due to the concern for all environmental changes that generate various human activities) [10], is the hypothesis that vaccination of natural reservoirs of host animals could stop the transmission of diseases to humans. Thus, vaccines targeted to wildlife reservoirs would affect the environment less and improve the health of the wild species

Rabies is a zoonotic disease characterized by acute and lethal encephalitis, and it is caused by rabies virus (RABV), a *Lyssavirus* from *Rhabdoviridae* family. Rabies occurs after bites or scratches from rabid animal [11]. As a result of the increase in the human population (together with their companion animals) and the invasion of natural habitats and other anthropogenic activities, such as the traffic of wild species, there is also a high risk in the exposure to infectious pathogens coming from the wildlife. In the last decades, the knowledge of the diseases produced in wild animals that could produce spillover phenomena in the human population and

The majority of cases of rabies in humans are transmitted by dogs. It has been estimated that infection causes 60,000 cases per year, mainly in Asian, African, and

There have been considerable efforts in vaccination campaigns in domestic fauna in the Americas, in order to control rabies virus transmission [13, 14]. However, wild mammals such as bats and carnivores play an important role in transmission to humans, particularly bats constitute the principal rabies reservoir

In Europe, during the 1960s, the only method used to contain wild rabies transmitted by red foxes was capturing and poisoning. However, it was an expensive and inefficient method in the long term [18]. One of the most cost-effective mechanisms to prevent the transmission of infection diseases is immunization. Since then, several approaches had been made for vaccination in the field with low effectiveness [18]. Nevertheless, the oral infection of mice coupled with the development of attenuated rabies strains gave the guideline for oral rabies vaccination (ORV) in

Since the end of the 1970s, the ORV by means of baits was implemented in Europe using live attenuated rabies virus from 11 different strains, of which SAD Bern and SAD B19 were the most used [21]. This vaccination strategy resulted in the reduction of rabies by 80% and the eradication of the rabies disease in foxes in Western and Central Europe. In this regard, calendar of vaccination campaigns, the adequate distribution and density of baits, as well as the duration and follow-up of

In the United States of America and Canada, the success story with ORV was replicated with the use of recombinant vaccines, employing the vaccinia virus (VRG) and a human adenovirus (ONRAB) that expresses the RABV glycoprotein [24]. In this case, the ORV programs were targeted at raccoons, gray foxes, and coyotes [25]. However, chiropters and carnivores are the main host of Lyssaviruses,

As the European case, in Latin-American countries, the rabies control has been based in reservoir population reduction which means bat population reduction using anticoagulants [26]. Some approximations have been made for the development of ORV for bats taking advantage of the habit of constant grooming and close contact with other members of the population [27]; the recombinant vaccine is

and major spillover events have been detected from bats to carnivores [25].

*DOI: http://dx.doi.org/10.5772/intechopen.84765*

zoonoses has been of special interest [12].

the ORV campaigns, were considered [21–23].

American countries, [13].

in the Americas [15–17].

wildlife [18–20].

in order to improve our health.

**4. Rabies**

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future… DOI: http://dx.doi.org/10.5772/intechopen.84765*

The idea of One Health program, recently developed and adopted (due to the concern for all environmental changes that generate various human activities) [10], is the hypothesis that vaccination of natural reservoirs of host animals could stop the transmission of diseases to humans. Thus, vaccines targeted to wildlife reservoirs would affect the environment less and improve the health of the wild species in order to improve our health.

#### **4. Rabies**

*Vaccines - The History and Future*

America and Andes in South America [7].

those who produce HCPS (Sin Nombre and Andes) [7].

reservoir (in this case rodents) is an option that should be considered.

the case of attenuated vaccines) may not reach the desired species.

for veterinary use is lower, among other things [9].

**3. Vaccines against hantavirus**

and large (L) [1, 2]. Unlike the other genera in the family, the hantaviruses are not transmitted by arthropods; their hosts are rodents and insectivores, and there is often an association of a type of virus with a host species [2]. In addition, new hantaviruses have been described in moles and shrews, as well as in bats, which increases the host range [3, 4]. Hantaviruses are maintained in rodent populations asymptomatic. Human infections are accidental (spillover), since for epidemiology and/or virus transmission cycle, the latter are a dead end (except for the case of Andes virus, where humanhuman transmission has been reported) [1, 5]. Transmissions among organisms occur by aerosol exposure, either by urine, feces, or saliva of infected animals, mainly [1]. In rodents, hantavirus infection has an acute phase (peak viremia) during first 2–3 weeks, with virus replication in target tissues and finally a persistent infection [1]. In humans, hantavirus infection can produce two presentations of the disease, depending on the type of virus with which it is infected: hemorrhagic fever with renal syndrome (HFRS) that occurs in Europe and Asia (Old World) mainly and the syndrome cardiopulmonary by hantavirus (HCPS) reported in the Americas (New World) [6]. It is important to note that HFRS can be caused by different viruses, the most common being Puumala and Dobrava in Europe and Hantaan and Seoul in Asia, while for the HCPS, the most common and lethal are *Sin Nombre* in North

Currently, vaccine for humans approved by the FDA or any other institution for use in the USA or Europe is not available. An inactivated virus vaccine produced in mouse brain or in cell culture infected with Hantaan virus (HFRS vaccine) is applied in China and Korea. However, this vaccine may not be as effective against the other viruses that produce HFRS in Europe (Puumala and Dobrava) and not for

Considering the variety of hantaviruses and hosts, as well as the fact that there is no authorized or commercialized vaccine for human use that protects against all types of hantavirus, the development of a vaccine that can be applied to the natural

When talking about vaccinating wildlife, the best option is the use of baits, which contain antigenic vaccine material, with stability under different environmental conditions. Since the capture and direct application of a vaccine would be unfeasible and the dispersion by a liquid or air (aerosol) constitutes a not selective administration, which might reach undesirable species and risk the risk of adverse effect, dispersion of the vaccine in species that had not been in contact naturally (in

The viral target to which the vaccines are directed could be the Gn and Gc glycoproteins, which interact with the cellular receptor (integrins) for the entry of the virus into the cell [8]. We must consider the variability among the hantaviruses that can infect humans, since, as mentioned above, the vaccine applied in China and Korea runs the risk that, if it is not well designed, different vaccines against the hantavirus should be applied according to the region. Another point to consider in the design of this vaccine is the host variability that hantaviruses have as a group [6]. Mendoza et al. [9] described several characteristics desirable in the vaccine baits, such as having palatable baits for different species and stability of the vaccine in different environmental conditions among others. Development vaccine for animal use is faster in the process approval for commercial use. In this regard, the cost-benefit ratio is better, since the cost of production and distribution of a vaccine

**44**

Rabies is a zoonotic disease characterized by acute and lethal encephalitis, and it is caused by rabies virus (RABV), a *Lyssavirus* from *Rhabdoviridae* family. Rabies occurs after bites or scratches from rabid animal [11]. As a result of the increase in the human population (together with their companion animals) and the invasion of natural habitats and other anthropogenic activities, such as the traffic of wild species, there is also a high risk in the exposure to infectious pathogens coming from the wildlife. In the last decades, the knowledge of the diseases produced in wild animals that could produce spillover phenomena in the human population and zoonoses has been of special interest [12].

The majority of cases of rabies in humans are transmitted by dogs. It has been estimated that infection causes 60,000 cases per year, mainly in Asian, African, and American countries, [13].

There have been considerable efforts in vaccination campaigns in domestic fauna in the Americas, in order to control rabies virus transmission [13, 14]. However, wild mammals such as bats and carnivores play an important role in transmission to humans, particularly bats constitute the principal rabies reservoir in the Americas [15–17].

In Europe, during the 1960s, the only method used to contain wild rabies transmitted by red foxes was capturing and poisoning. However, it was an expensive and inefficient method in the long term [18]. One of the most cost-effective mechanisms to prevent the transmission of infection diseases is immunization. Since then, several approaches had been made for vaccination in the field with low effectiveness [18].

Nevertheless, the oral infection of mice coupled with the development of attenuated rabies strains gave the guideline for oral rabies vaccination (ORV) in wildlife [18–20].

Since the end of the 1970s, the ORV by means of baits was implemented in Europe using live attenuated rabies virus from 11 different strains, of which SAD Bern and SAD B19 were the most used [21]. This vaccination strategy resulted in the reduction of rabies by 80% and the eradication of the rabies disease in foxes in Western and Central Europe. In this regard, calendar of vaccination campaigns, the adequate distribution and density of baits, as well as the duration and follow-up of the ORV campaigns, were considered [21–23].

In the United States of America and Canada, the success story with ORV was replicated with the use of recombinant vaccines, employing the vaccinia virus (VRG) and a human adenovirus (ONRAB) that expresses the RABV glycoprotein [24]. In this case, the ORV programs were targeted at raccoons, gray foxes, and coyotes [25]. However, chiropters and carnivores are the main host of Lyssaviruses, and major spillover events have been detected from bats to carnivores [25].

As the European case, in Latin-American countries, the rabies control has been based in reservoir population reduction which means bat population reduction using anticoagulants [26]. Some approximations have been made for the development of ORV for bats taking advantage of the habit of constant grooming and close contact with other members of the population [27]; the recombinant vaccine is

mixed with petrolatum paste or glycerin jelly and applied topically on the back of a bat vector [28–30]. These works are carried out in controlled environments with promising results, obtaining survival rates between 80 to 70% in *Eptesicus fuscus* bats and 70 to 100% in *Desmodus rotundus* [28–30].

#### **5. Hepatitis E**

Hepatitis E is a liver disease caused by infection with a virus known as hepatitis E virus (HEV), globally considered as an emerging public health problem [31]. While hepatitis E is considered as self-limited liver disease in humans, it can evolve as a chronic liver disease, whose complications are responsible for 44,000 deaths in 2015 [31, 32]. HEV infection can be acquired by fecal-oral route or contaminated water and other routes less frequent, such as zoonotic via ingestion of undercooked meat or meat products derived from infected animals, transfusion of infected blood products, and vertical transmission to fetus during pregnancy or occupational exposition [33, 34].

Since the first identification of HEV in 1983 [35], it was thought that the virus was only limited to animal species. However, in the recent years, an increasing number of HEV infections in humans have been reported [36–39]. Thus, and based on several anti-HEV antibody serosurveillance studies [37–46], it is important to highlight that the worldwide HEV prevalence seems to be higher than reported, as outbreaks or sporadic in pregnant women and immunocompromised patients [46–49].

This virus has a single, positive-stranded RNA genome of 7.2 kb in length. The genome contains three open reading frames (ORF1, ORF2, and ORF3). ORF2 encodes for viral capsid, which have immunogenic properties [50]. Hepatitis E virus is an RNA virus classified within the *Hepeviridae* family, belonging to the genus *Orthohepevirus* [51]. Four species are recognized. *Orthohepevirus A* viruses has been identified in several mammals, such as swine, wild boars, mongoose, camels, rabbits, and humans. In this regard, swine is considered the main reservoir, and the consumption of uncooked pork products has been associated with the disease [52]. *Orthohepevirus* A is divided into eight genotypes of HEV (HEV-1 to HEV-8). HEV-1 and HEV-2 genotypes can infect humans, while HEV-3 and HEV-4 have been isolated from humans, swine, and wild boars, being HEV-3 the genotype with the highest worldwide distribution [53].

**47**

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future…*

Genotypes HEV-5 and HEV-6 have been identified in wild boars, while HEV-7 and HEV-8 genotypes are isolated from camelids (**Figure 1**) [54]. *Orthohepevirus B* viruses infect mainly birds, *Orthohepevirus* C viruses infect rodents, and *Orthohepevirus* D virus has been restricted to bats [55]. Although a majority of species mentioned above are not in close contact with humans, some of them participate as intermediate hosts,

Vaccines represent the most effective prophylactic approach against several viral infections. Current WHO position considers vaccination against HEV [13], in order to prevent disease in high-risk groups such as pregnant women and immunocompromised individual. In this regard, anti-HEV recombinant vaccine, based on the capsid protein, was developed, showing efficacy of 88.5% [57]. In addition, a vaccine, anti-HEV 239 Hecolin (Xiamen Innovax Biotech), based in two epitopes from capsid (368–606 aa of ORF2), of genotype HEV-1, was only approved in China, with an efficacy of 86.8% [58, 59]. DNA anti-HEV vaccines have been developed (**Table 1**). In this regard, DNA vaccines have some advantages over use of attenuated viruses, besides to their stability at room temperature, making more affordable at veterinary field and the wildlife [60]. Thus, the delivery system for vaccination and genetic diversity of HEV must be considered in order to develop effective vac-

Finally, like the control strategies of wildlife rabies [65], the use of vaccine-laden bait delivery to intermediate hosts represents attractive alternatives useful to reduce the spread of HEV RABV circulation. While this approach is promising, it remains

**Example Immune response Host Reference** DNA vaccine ORF2 gene (1–660 amino acids, aa) Anti-HEV IgG Mouse [61]

IgG antibodies Mouse [62]

Rhesus monkey

monkey

[63]

[64]

IgG-neutralizing antibodies

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus), belonging to the family *Flaviviridae*, which was first isolated from a rhesus monkey in the Zika forest of Uganda in 1952 [66]. Since Brazil reported in 2015, the association ZIKV infection and microcephaly [67]; outbreaks and evidence of their transmission in many areas of Americas Africa and other regions have been reported [68]. Although ZIKV infection is considered as self-limited illness and minimally symptomatic for most individuals, it can be threatening for human health worldwide, in particular to unborn fetus [69].

Capsid protein/ORF2 HEV genotype 4 Anti-HEV IgG Rhesus

cines, especially in intermediate hosts such swine or wildlife reservoirs.

*DOI: http://dx.doi.org/10.5772/intechopen.84765*

thus causing infection in humans [56].

**6. Vaccines anti-HEV**

to be investigated.

pseudoviruses

(1983 bp) in pVax plasmid

*Experimental anti-HEV vaccines.*

DNA vaccine based on HEV genes ORF2

DNA vaccine based on complete ORF2 gene

(112–660) and ORF2(112–608), using papillomavirus

**7. Zika vaccines**

**Table 1.**

**Figure 1.** *Worldwide distribution of HEV and their reservoirs in the wildlife.*

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future… DOI: http://dx.doi.org/10.5772/intechopen.84765*

Genotypes HEV-5 and HEV-6 have been identified in wild boars, while HEV-7 and HEV-8 genotypes are isolated from camelids (**Figure 1**) [54]. *Orthohepevirus B* viruses infect mainly birds, *Orthohepevirus* C viruses infect rodents, and *Orthohepevirus* D virus has been restricted to bats [55]. Although a majority of species mentioned above are not in close contact with humans, some of them participate as intermediate hosts, thus causing infection in humans [56].

#### **6. Vaccines anti-HEV**

*Vaccines - The History and Future*

**5. Hepatitis E**

bats and 70 to 100% in *Desmodus rotundus* [28–30].

mixed with petrolatum paste or glycerin jelly and applied topically on the back of a bat vector [28–30]. These works are carried out in controlled environments with promising results, obtaining survival rates between 80 to 70% in *Eptesicus fuscus*

Hepatitis E is a liver disease caused by infection with a virus known as hepatitis E virus (HEV), globally considered as an emerging public health problem [31]. While hepatitis E is considered as self-limited liver disease in humans, it can evolve as a chronic liver disease, whose complications are responsible for 44,000 deaths in 2015 [31, 32]. HEV infection can be acquired by fecal-oral route or contaminated water and other routes less frequent, such as zoonotic via ingestion of undercooked meat or meat products derived from infected animals, transfusion of infected blood products, and vertical transmission to fetus during pregnancy or occupational exposition [33, 34]. Since the first identification of HEV in 1983 [35], it was thought that the virus was only limited to animal species. However, in the recent years, an increasing number of HEV infections in humans have been reported [36–39]. Thus, and based on several anti-HEV antibody serosurveillance studies [37–46], it is important to highlight that the worldwide HEV prevalence seems to be higher than reported, as outbreaks or

sporadic in pregnant women and immunocompromised patients [46–49].

This virus has a single, positive-stranded RNA genome of 7.2 kb in length. The genome contains three open reading frames (ORF1, ORF2, and ORF3). ORF2 encodes for viral capsid, which have immunogenic properties [50]. Hepatitis E virus is an RNA virus classified within the *Hepeviridae* family, belonging to the genus *Orthohepevirus* [51]. Four species are recognized. *Orthohepevirus A* viruses has been identified in several mammals, such as swine, wild boars, mongoose, camels, rabbits, and humans. In this regard, swine is considered the main reservoir, and the consumption of uncooked pork products has been associated with the disease [52]. *Orthohepevirus* A is divided into eight genotypes of HEV (HEV-1 to HEV-8). HEV-1 and HEV-2 genotypes can infect humans, while HEV-3 and HEV-4 have been isolated from humans, swine, and wild boars, being HEV-3 the genotype with the highest worldwide distribution [53].

**46**

**Figure 1.**

*Worldwide distribution of HEV and their reservoirs in the wildlife.*

Vaccines represent the most effective prophylactic approach against several viral infections. Current WHO position considers vaccination against HEV [13], in order to prevent disease in high-risk groups such as pregnant women and immunocompromised individual. In this regard, anti-HEV recombinant vaccine, based on the capsid protein, was developed, showing efficacy of 88.5% [57]. In addition, a vaccine, anti-HEV 239 Hecolin (Xiamen Innovax Biotech), based in two epitopes from capsid (368–606 aa of ORF2), of genotype HEV-1, was only approved in China, with an efficacy of 86.8% [58, 59]. DNA anti-HEV vaccines have been developed (**Table 1**). In this regard, DNA vaccines have some advantages over use of attenuated viruses, besides to their stability at room temperature, making more affordable at veterinary field and the wildlife [60]. Thus, the delivery system for vaccination and genetic diversity of HEV must be considered in order to develop effective vaccines, especially in intermediate hosts such swine or wildlife reservoirs.

Finally, like the control strategies of wildlife rabies [65], the use of vaccine-laden bait delivery to intermediate hosts represents attractive alternatives useful to reduce the spread of HEV RABV circulation. While this approach is promising, it remains to be investigated.


#### **Table 1.**

*Experimental anti-HEV vaccines.*

#### **7. Zika vaccines**

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus), belonging to the family *Flaviviridae*, which was first isolated from a rhesus monkey in the Zika forest of Uganda in 1952 [66]. Since Brazil reported in 2015, the association ZIKV infection and microcephaly [67]; outbreaks and evidence of their transmission in many areas of Americas Africa and other regions have been reported [68]. Although ZIKV infection is considered as self-limited illness and minimally symptomatic for most individuals, it can be threatening for human health worldwide, in particular to unborn fetus [69].

Because arboviruses are often maintained in complex cycles involving vertebrates and blood-feeding vectors, not only humans are at high risk of ZIKV infection but also another species such as monkeys, domestic sheep, goats, horses, cows, ducks, rodents, bats, orangutans, and carabaos [69]. ZIKV infection has likely been present in bats since time. In this regard, anti-ZIKV antibodies with cross-reactivity to flaviviruses (yellow fever virus, West Nile virus, among others) were detected in bats from Uganda and Angola [70, 71]. Although it is unclear how ZIKV could circulate in bat populations, it is noteworthy that bats represent a competent reservoirs in wildlife, with potential for amplifying flaviviruses and, contributing thus in the sylvatic transmission of ZIKV [72]. In contrast, Bittar et al. [73] did not find serological and molecular evidence of past or latent arbovirus infections in captured bats from many areas of Brazil. Nevertheless, future studies are required to evaluate the role of bats as arbovirus reservoirs and to determine if these animal species are an important part of enzootic cycle of arboviruses [72].

Currently, there are no approved vaccines available to protect against infection. Unlikely to other antiviral vaccines, Zika vaccination must be approached mainly for the prevention of vertical transmission of the virus to the unborn fetus [74].

Finally, as long as a prophylactic vaccine is developed, it is important to consider that ZIKV is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are endemic. In this regard, Zika virus is closely related to other flaviviruses, and cross-reactive antibody has the potential to exacerbate secondary flavivirus infections through antibody-dependent enhancement (ADE), leading to more severe forms of flavivirus disease [75].

#### **8. Ebola and SARS-CoV vaccines**

Ebola is a viral illness caused by *Ebola virus*. Five species of the genus *Ebolavirus* from Africa have been recognized, *Zaire ebolavirus* (ZEBOV), *Sudan ebolavirus* (SEBOV), *Cote d'Ivoire ebolavirus* (CEBOV), *Bundibugyo ebolavirus* (BEBOV), and *Reston ebolavirus* (REBOV), all belonging to *Filoviridae* family. Viral replication have a lethal nature, which involve necrosis of several lymph organs, kidneys, liver, testes, and ovaries; changes in vascular permeability; activation of the clotting cascade; and damage in platelets, among others [76]. Although the natural reservoir of the virus is unknown, it is assumed that bats represent a natural reservoir in the wildlife species, without causing disease [77], highlighting extensive coevolution of Ebola virus and bats, over time [76]. Therefore, feasibility of Ebola vaccine must focus on the prevention of Ebola in endemic areas as well as usage during sporadic outbreaks in humans [78]. Ideally, candidate vaccine must be able to confer interspecies cross-protection against SEBOV, BEBOV, and ZEBOV [76].

With respect to SARS-CoV, the development of a vaccine that is applied to wild vectors is a little more complex. Bats have been proposed as potential reservoirs, and there may be an intermediate host, such as civets [79]. However, there are still epidemiological studies that help us understand the dynamics of animals, *coronavirus*, and humans, in order to establish the best vaccination strategy, since not all zoonotic disease vector vaccination can be the solution.

#### **9. Conclusions**

Hantavirus, RABV, HEV, ZIKV, Ebola virus, and SARS-CoV are currently considered as emerging infectious pathogens to humans, whose reservoirs are in wildlife animals. While the transmission of these viruses from wildlife reservoirs to human

**49**

**Author details**

Salas-Rojas Mónica1

Mexico City, México

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Unidad de Investigación en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, México

2 Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,

and Pompa-Mera Ericka Nelly2

\*

, Gálvez-Romero Guillermo1

\*Address all correspondence to: erickanelly@yahoo.com.mx

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future…*

is rare, it is important to develop control strategies in order to reduce the substantial impacts on human health and agricultural production. In several cases, such as rabies disease the vaccines targeted to wildlife reservoirs, represent a control measure friendly with the environment, in virtue of they help to the conservation of healthy habitats with available niches and wild prey for bats, avoiding the migration of these

*DOI: http://dx.doi.org/10.5772/intechopen.84765*

species to another areas.

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future… DOI: http://dx.doi.org/10.5772/intechopen.84765*

is rare, it is important to develop control strategies in order to reduce the substantial impacts on human health and agricultural production. In several cases, such as rabies disease the vaccines targeted to wildlife reservoirs, represent a control measure friendly with the environment, in virtue of they help to the conservation of healthy habitats with available niches and wild prey for bats, avoiding the migration of these species to another areas.

#### **Author details**

*Vaccines - The History and Future*

part of enzootic cycle of arboviruses [72].

**8. Ebola and SARS-CoV vaccines**

against SEBOV, BEBOV, and ZEBOV [76].

zoonotic disease vector vaccination can be the solution.

Because arboviruses are often maintained in complex cycles involving vertebrates and blood-feeding vectors, not only humans are at high risk of ZIKV infection but also another species such as monkeys, domestic sheep, goats, horses, cows, ducks, rodents, bats, orangutans, and carabaos [69]. ZIKV infection has likely been present in bats since time. In this regard, anti-ZIKV antibodies with cross-reactivity to flaviviruses (yellow fever virus, West Nile virus, among others) were detected in bats from Uganda and Angola [70, 71]. Although it is unclear how ZIKV could circulate in bat populations, it is noteworthy that bats represent a competent reservoirs in wildlife, with potential for amplifying flaviviruses and, contributing thus in the sylvatic transmission of ZIKV [72]. In contrast, Bittar et al. [73] did not find serological and molecular evidence of past or latent arbovirus infections in captured bats from many areas of Brazil. Nevertheless, future studies are required to evaluate the role of bats as arbovirus reservoirs and to determine if these animal species are an important

Currently, there are no approved vaccines available to protect against infection. Unlikely to other antiviral vaccines, Zika vaccination must be approached mainly for the prevention of vertical transmission of the virus to the unborn fetus [74]. Finally, as long as a prophylactic vaccine is developed, it is important to consider that ZIKV is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are endemic. In this regard, Zika virus is closely related to other flaviviruses, and cross-reactive antibody has the potential to exacerbate secondary flavivirus infections through antibody-dependent enhancement (ADE), leading to more severe forms of flavivirus disease [75].

Ebola is a viral illness caused by *Ebola virus*. Five species of the genus *Ebolavirus* from Africa have been recognized, *Zaire ebolavirus* (ZEBOV), *Sudan ebolavirus* (SEBOV), *Cote d'Ivoire ebolavirus* (CEBOV), *Bundibugyo ebolavirus* (BEBOV), and *Reston ebolavirus* (REBOV), all belonging to *Filoviridae* family. Viral replication have a lethal nature, which involve necrosis of several lymph organs, kidneys, liver, testes, and ovaries; changes in vascular permeability; activation of the clotting cascade; and damage in platelets, among others [76]. Although the natural reservoir of the virus is unknown, it is assumed that bats represent a natural reservoir in the wildlife species, without causing disease [77], highlighting extensive coevolution of Ebola virus and bats, over time [76]. Therefore, feasibility of Ebola vaccine must focus on the prevention of Ebola in endemic areas as well as usage during sporadic outbreaks in humans [78]. Ideally, candidate vaccine must be able to confer interspecies cross-protection

With respect to SARS-CoV, the development of a vaccine that is applied to wild vectors is a little more complex. Bats have been proposed as potential reservoirs, and there may be an intermediate host, such as civets [79]. However, there are still epidemiological studies that help us understand the dynamics of animals, *coronavirus*, and humans, in order to establish the best vaccination strategy, since not all

Hantavirus, RABV, HEV, ZIKV, Ebola virus, and SARS-CoV are currently considered as emerging infectious pathogens to humans, whose reservoirs are in wildlife animals. While the transmission of these viruses from wildlife reservoirs to human

**48**

**9. Conclusions**

Salas-Rojas Mónica1 , Gálvez-Romero Guillermo1 and Pompa-Mera Ericka Nelly2 \*

1 Unidad de Investigación en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, México

2 Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, México

\*Address all correspondence to: erickanelly@yahoo.com.mx

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Allendorf SD, Cortez A, Heinemann MB, Harary CM, Antunes JM, Peres MG, et al. Rabies virus distribution in tissues and molecular characterization of strains from naturally infected nonhematophagous bats. Virus Research. 2012;**165**(2):119-125. DOI: 10.1016/j. virusres.2012.01.011

[18] Baer GM. In: Baer GM, editor. The Natural History of Rabies. Vol. 2. New York: Academic; 1975. pp. 261-266

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[20] Baer GM, Abelseth MK, Debbie JG. Oral vaccination of foxes against rabies. American Journal of Epidemiology. 1971;**93**(6):487-490

[21] Müller TF, Schröder R, Wysocki P, Mettenleiter TC, Freuling CM. Spatiotemporal use of oral rabies vaccines in fox rabies elimination programmes in Europe. PLoS Neglected Tropical Diseases. 2015;**9**(8):e0003953. DOI: 10.1371/journal.pntd.0003953

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[29] Stading B, Ellison JA, Carson WC, Satheshkumar PS, Rocke TE, Osorio JE. Protection of bats (*Eptesicus fuscus*) against rabies following topical or oronasal exposure to a recombinant raccoon poxvirus vaccine. PLoS Neglected Tropical Diseases. 2017;**11**(10):e0005958. DOI: 10.1371/ journal.pntd.0005958

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[31] WHO, 2017. Available online:http:// www.who.int/en/news-room/

**50**

erv.12.15

*Vaccines - The History and Future*

[1] Easterbrook JD, Klein SL. Immunological mechanisms mediating hantavirus persistence in rodent reservoirs. PLoS Pathogens. 2008;**4**(11):e1000172. DOI: 10.1371/

[2] International Committee on Taxonomy of Viruses (ICTV).

[Accessed: December 10, 2018]

10.1371/journal.ppat.1003159

Available in: https://talk.ictvonline.org/

[9] Mendoza EJ, Warner B, Kobinger G,

Ogden NH, Safronetz D. Baited vaccines: A strategy to mitigate rodentborne viral zoonoses in humans. Zoonoses and Public Health. 2018. In

press. DOI: 10.1111/zph.12487

10.1371/journal.pntd.0003257

10.1007/978-3-319-33133-1\_4

pntd.0003257

fact-sheets/detail/rabies

[12] Gebreyes WA, Dupouy-Camet J, Newport MJ, Oliveira CJ, Schlesinger LS, Saif YM, et al. The global one health paradigm: Challenges and opportunities for tackling infectious diseases at the human, animal, and environment interface in low-resource settings. PLoS Neglected Tropical Diseases. 2014;**8**(11):e3257. DOI: 10.1371/journal.

[13] WHO. 2017. http://www.who.int/ rabies/epidemiology/en/ Available in: https://www.who.int/news-room/

[14] de Thoisy B, Bourhy H, Delaval M, Pontier D, Dacheux L, Darcissac E, et al. Bioecological drivers of rabies virus circulation in a neotropical bat community. PLoS Neglected Tropical Diseases. 2016;**10**(1):e0004378. DOI: 10.1371/journal.pntd.0004378

[15] Rupprecht CE, Hanlon CA, Hemachudha T. Rabies re-examined. The Lancet Infectious Diseases.

2002;**2**(6):327-343

[11] Lafon M. Rabies. In: Reiss CS, editor. Neurotropic Viral Infections. Vol. 85. Switzerland: Springer International Publishing; 2016, 2016. pp. 85-113. DOI:

[10] Gebreyes WA, Dupouy-Camet J, Newport MJ, Oliveira CJ, Schlesinger LS, Saif YM, et al. The global one health paradigm: Challenges and opportunities for tackling infectious diseases at the human, animal, and environment interface in low-resource settings. PLoS Neglected Tropical Diseases. 2014;**8**(11):e3257. DOI:

[3] Guo WP, Lin XD, Wang W, Tian JH, Cong ML, Zhang HL, et al. Phylogeny and origins of hantaviruses harbored by bats, insectivores, and rodents. PLoS Pathogens. 2013;**9**(2):e1003159. DOI:

[4] Sabino-Santos G Jr, Maia FG, Vieira TM, de Lara Muylaert R, Lima SM, Gonçalves CB, et al. Evidence of hantavirus infection among bats in Brazil. The American Journal of Tropical Medicine and Hygiene. 2015;**93**(2): 404-406. DOI: 10.4269/ajtmh.15-0032

[5] Martinez VP, Bellomo C, San Juan J, Pinna D, Forlenza R, Elder M, et al. Person-to-person transmission of Andes virus. Emerging Infectious Diseases.

[6] Ermonval M, Baychelier F, Tordo N.

[8] Cifuentes-Muñoz N, Salazar-Quiroz N, Tischler ND. Hantavirus Gn and Gc envelope glycoproteins: Key structural units for virus cell entry and virus assembly. Viruses. 2014;**6**(4):1801-1822.

2005;**11**(12):1848-1853

What do we know about how hantaviruses interact with their different hosts? Viruses. 2016;**11**(8):8,

E223. DOI: 10.3390/v8080223

[7] Schmaljohn CS. Vaccines for hantaviruses: Progress and issues. Expert Review of Vaccines. 2012;**11**(5):511-513. DOI: 10.1586/

DOI: 10.3390/v6041801

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[32] Rowe IA. Lessons from epidemiology: The burden of liver disease. Digestive Diseases. 2017;**35**(4):304-309. DOI: 10.1159/000456580

[33] Meng XJ, Wiseman B, Elvinger F, Guenette DK, Toth TE, Engle RE, et al. Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. Journal of Clinical Microbiology. 2002;**40**(1):117-122

[34] Farshadpour F, Taherkhani S, Taherkhani R. Hepatitis E virus infection during pregnancy: The overlooked cause of maternal and fetal mortality. Infectious Disorders Drug Targets. 2018; In press. DOI: 10.2174/187 1526518666180530075523

[35] Balayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, et al. Evidence for a virus in non-a, non-B hepatitis transmitted via the fecal-oral route. Intervirology. 1983;**20**(1):23-31

[36] Renou C, Lafeuillade A, Cadranel JF, Pavio N, Pariente A, Allègre T, et al. E virus in HIV-infected patients. AIDS. 2010;**24**(10):1493-1499. DOI: 10.1097/ QAD.0b013e32833a29ab

[37] Lee GH, Tan BH, Teo EC, Lim SG, Dan YY, Wee A, et al. Chronic infection with Camelid Hepatitis E virus in a liver transplant recipient who regularly consumes camel meat and Milk. Gastroenterology. 2016;**150**(2):355, e3-357. DOI: 10.1053/j. gastro.2015.10.048

[38] Kamar N, Izopet J, Pavio N, Aggarwal R, Labrique A, Wedemeyer H, et al. Hepatitis E virus infection. Nature Reviews. Disease Primers. 2017;**3**:17086. DOI: 10.1038/nrdp.2017.86

[39] Zhou S, Ren L, Xia X, Miao Z, Huang F, Li Y, et al. Hepatitis E virus infection in HIV-infected patients: A large cohort study in Yunnan province, China. Journal of Medical Virology. 2018;**90**(6):1121-1127. DOI: 10.1002/ jmv.25060

[40] Christensen PB, Engle RE, Hjort C, Homburg KM, Vach W, Georgsen J, et al. Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: A potential zoonosis in Denmark. Clinical Infectious Diseases. 2008;**47**(8):1026-1031. DOI: 10.1086/591970

[41] Mansuy JM, Legrand-Abravanel F, Calot JP, Peron JM, Alric L, Agudo S, et al. High prevalence of anti-hepatitis E virus antibodies in blood donors from south West France. Journal of Medical Virology. 2008;**80**(2):289-293

[42] Lucarelli C, Spada E, Taliani G, Chionne P, Madonna E, Marcantonio C, et al. High prevalence of anti-hepatitis E virus antibodies among blood donors in Central Italy, February to march 2014. Euro Surveillance. 2016;**21**(30). DOI: 10.2807/1560-7917.ES.2016.21.30.30299

[43] Aydin H, Uyanik MH, Karamese M, Timurkan MO. Seroprevalence of Hepatitis E Virus in humans working with animals in non-porcine consumption areas of Turkey. Poster P-1425 presented in 26th European Congress of Clinical Microbiology and Infectious Diseases, 09-12 April 2016, Amsterdam, Netherlands

[44] Bura M, Bukowska A, Bura A, Michalak M, Mozer-Lisewska I. Hepatitis E virus antibodies in HIVinfected patients and blood donors from western Poland: A preliminary report. Advances in Clinical and Experimental Medicine. 2017;**26**(4):577-579. DOI: 10.17219/acem/62353

[45] Zeng H, Wang L, Liu P, Liao L, Wang L, Shao Y. Seroprevalence

**53**

eid2011.140791

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future…*

2223-2232

JVI.00800-12

[53] Smith DB, Simmonds P,

International Committee on Taxonomy of Viruses Hepeviridae Study Group, Jameel S, Emerson SU, Harrison TJ, et al. Consensus proposals for classification of the family Hepeviridae. The Journal of General Virology. 2014;**95**(Pt 10):

[54] Pavio N, Doceul V, Bagdassarian E,

[55] Drexler JF, Seelen A, Corman VM, Fumie Tateno A, Cottontail V, Melim Zerbinati R, et al. Bats worldwide carry hepatitis E virus-related viruses that form a putative novel genus within the family Hepeviridae. Journal of Virology. 2012;**86**(17):9134-9147. DOI: 10.1128/

[56] Han HJ, Wen HL, Zhou CM, Chen FF, Luo LM, Liu JW, et al. Bats as reservoirs of severe emerging infectious diseases. Virus Research. 2015;**205**:1-6. DOI: 10.1016/j.virusres.2015.05.006

[57] Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, et al. Safety and efficacy of a recombinant hepatitis E vaccine. The New England Journal of Medicine.

[58] Zhu FC, Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: A large-scale, randomised, double-blind placebocontrolled, phase 3 trial. Lancet. 2010;**376**(9744):895-902. DOI: 10.1016/

[59] Zhang J, Zhang XF, Huang SJ, Wu T, Hu YM, Wang ZZ, et al. Long-term efficacy of a hepatitis E vaccine. The New England Journal of Medicine. 2015;**372**(10):914-922. DOI: 10.1056/

2007;**356**(9):895-903

S0140-6736(10)61030-6

NEJMoa1406011

 Johne R. Recent knowledge on hepatitis E virus in Suidae reservoirs and transmission routes to human. Veterinary Research. 2017;**48**(1):78. DOI: 10.1186/s13567-017-0483-9

*DOI: http://dx.doi.org/10.5772/intechopen.84765*

[46] Andersson MI, Stead PA, Maponga T, van der Plas H, Preiser W. Hepatitis E virus infection: An underdiagnosed infection in transplant patients in southern Africa? Journal of Clinical Virology. 2015;**70**:23-25. DOI: 10.1016/j.

[47] Schulz M, Beha D, Plehm K, Zöllner C, Hofmann J, Schott E. High prevalence of anti-hepatitis E virus antibodies in outpatients with chronic liver disease in a university medical center in Germany. European Journal of Gastroenterology & Hepatology.

[48] Abravanel F, Lhomme S, Fougère M, Saune K, Alvarez M, Péron JM, et al. HEV infection in French HIV-infected patients. The Journal of Infection. 2017;**74**(3):310-313. DOI: 10.1016/j.

[49] Farshadpour F, Taherkhani S, Taherkhani R. Hepatitis E virus infection during pregnancy: The overlooked cause of maternal and fetal mortality. Infectious Disorders Drug Targets. 2018, . In press. DOI: 10.2174/18

[50] Khuroo MS, Khuroo MS, Khuroo NS. Hepatitis E: Discovery, global impact, control and cure. World Journal of Gastroenterology. 2016;**22**(31):7030- 7045. DOI: 10.3748/wjg.v22.i31.7030

[51] Panda SK, Thakral D, Rehman S. Hepatitis E virus. Reviews in Medical

Virology. 2007;**17**(3):151-180

[52] Roque-Afonso AM, Pavio N. Foodborne transmission of hepatitis E virus from raw pork liver sausage, France. Emerging Infectious Diseases. 2014;**20**(11):1945-1947. DOI: 10.3201/

71526518666180530075523

of hepatitis E virus in HIVinfected patients in China. AIDS. 2017;**31**(14):2019-2021. DOI: 10.1097/

QAD.0000000000001585

jcv.2015.06.081

2016;**28**(12):1431-1436

jinf.2016.12.004

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future… DOI: http://dx.doi.org/10.5772/intechopen.84765*

of hepatitis E virus in HIVinfected patients in China. AIDS. 2017;**31**(14):2019-2021. DOI: 10.1097/ QAD.0000000000001585

*Vaccines - The History and Future*

on 10 December 2018)

2002;**40**(1):117-122

1526518666180530075523

QAD.0b013e32833a29ab

gastro.2015.10.048

[32] Rowe IA. Lessons from epidemiology: The burden of liver disease. Digestive Diseases. 2017;**35**(4):304-309. DOI: 10.1159/000456580

fact-sheets/detail/hepatitis-e (Accessed

[39] Zhou S, Ren L, Xia X, Miao Z, Huang F, Li Y, et al. Hepatitis E virus infection in HIV-infected patients: A large cohort study in Yunnan province, China. Journal of Medical Virology. 2018;**90**(6):1121-1127. DOI: 10.1002/

[40] Christensen PB, Engle RE, Hjort C, Homburg KM, Vach W, Georgsen J, et al. Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: A potential zoonosis

[41] Mansuy JM, Legrand-Abravanel F, Calot JP, Peron JM, Alric L, Agudo S, et al. High prevalence of anti-hepatitis E virus antibodies in blood donors from south West France. Journal of Medical

in Denmark. Clinical Infectious Diseases. 2008;**47**(8):1026-1031. DOI:

Virology. 2008;**80**(2):289-293

[42] Lucarelli C, Spada E, Taliani G, Chionne P, Madonna E, Marcantonio C, et al. High prevalence of anti-hepatitis E virus antibodies among blood donors in Central Italy, February to march 2014. Euro Surveillance. 2016;**21**(30). DOI: 10.2807/1560-7917.ES.2016.21.30.30299

[43] Aydin H, Uyanik MH, Karamese M,

Timurkan MO. Seroprevalence of Hepatitis E Virus in humans working with animals in non-porcine consumption areas of Turkey. Poster P-1425 presented in 26th European Congress of Clinical Microbiology and Infectious Diseases, 09-12 April 2016,

Amsterdam, Netherlands

10.17219/acem/62353

[44] Bura M, Bukowska A, Bura A, Michalak M, Mozer-Lisewska

I. Hepatitis E virus antibodies in HIVinfected patients and blood donors from western Poland: A preliminary report. Advances in Clinical and Experimental Medicine. 2017;**26**(4):577-579. DOI:

[45] Zeng H, Wang L, Liu P, Liao L, Wang L, Shao Y. Seroprevalence

jmv.25060

10.1086/591970

[33] Meng XJ, Wiseman B, Elvinger F, Guenette DK, Toth TE, Engle RE, et al. Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. Journal of Clinical Microbiology.

[34] Farshadpour F, Taherkhani S, Taherkhani R. Hepatitis E virus infection during pregnancy: The overlooked cause of maternal and fetal mortality. Infectious Disorders Drug Targets. 2018; In press. DOI: 10.2174/187

[35] Balayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, et al. Evidence for a virus in non-a, non-B hepatitis transmitted via the fecal-oral route. Intervirology. 1983;**20**(1):23-31

[36] Renou C, Lafeuillade A, Cadranel JF, Pavio N, Pariente A, Allègre T, et al. E virus in HIV-infected patients. AIDS. 2010;**24**(10):1493-1499. DOI: 10.1097/

[37] Lee GH, Tan BH, Teo EC, Lim SG,

Dan YY, Wee A, et al. Chronic infection with Camelid Hepatitis E virus in a liver transplant recipient who regularly consumes camel meat and Milk. Gastroenterology. 2016;**150**(2):355, e3-357. DOI: 10.1053/j.

[38] Kamar N, Izopet J, Pavio N,

DOI: 10.1038/nrdp.2017.86

Aggarwal R, Labrique A, Wedemeyer H, et al. Hepatitis E virus infection. Nature Reviews. Disease Primers. 2017;**3**:17086.

**52**

[46] Andersson MI, Stead PA, Maponga T, van der Plas H, Preiser W. Hepatitis E virus infection: An underdiagnosed infection in transplant patients in southern Africa? Journal of Clinical Virology. 2015;**70**:23-25. DOI: 10.1016/j. jcv.2015.06.081

[47] Schulz M, Beha D, Plehm K, Zöllner C, Hofmann J, Schott E. High prevalence of anti-hepatitis E virus antibodies in outpatients with chronic liver disease in a university medical center in Germany. European Journal of Gastroenterology & Hepatology. 2016;**28**(12):1431-1436

[48] Abravanel F, Lhomme S, Fougère M, Saune K, Alvarez M, Péron JM, et al. HEV infection in French HIV-infected patients. The Journal of Infection. 2017;**74**(3):310-313. DOI: 10.1016/j. jinf.2016.12.004

[49] Farshadpour F, Taherkhani S, Taherkhani R. Hepatitis E virus infection during pregnancy: The overlooked cause of maternal and fetal mortality. Infectious Disorders Drug Targets. 2018, . In press. DOI: 10.2174/18 71526518666180530075523

[50] Khuroo MS, Khuroo MS, Khuroo NS. Hepatitis E: Discovery, global impact, control and cure. World Journal of Gastroenterology. 2016;**22**(31):7030- 7045. DOI: 10.3748/wjg.v22.i31.7030

[51] Panda SK, Thakral D, Rehman S. Hepatitis E virus. Reviews in Medical Virology. 2007;**17**(3):151-180

[52] Roque-Afonso AM, Pavio N. Foodborne transmission of hepatitis E virus from raw pork liver sausage, France. Emerging Infectious Diseases. 2014;**20**(11):1945-1947. DOI: 10.3201/ eid2011.140791

[53] Smith DB, Simmonds P, International Committee on Taxonomy of Viruses Hepeviridae Study Group, Jameel S, Emerson SU, Harrison TJ, et al. Consensus proposals for classification of the family Hepeviridae. The Journal of General Virology. 2014;**95**(Pt 10): 2223-2232

[54] Pavio N, Doceul V, Bagdassarian E, Johne R. Recent knowledge on hepatitis E virus in Suidae reservoirs and transmission routes to human. Veterinary Research. 2017;**48**(1):78. DOI: 10.1186/s13567-017-0483-9

[55] Drexler JF, Seelen A, Corman VM, Fumie Tateno A, Cottontail V, Melim Zerbinati R, et al. Bats worldwide carry hepatitis E virus-related viruses that form a putative novel genus within the family Hepeviridae. Journal of Virology. 2012;**86**(17):9134-9147. DOI: 10.1128/ JVI.00800-12

[56] Han HJ, Wen HL, Zhou CM, Chen FF, Luo LM, Liu JW, et al. Bats as reservoirs of severe emerging infectious diseases. Virus Research. 2015;**205**:1-6. DOI: 10.1016/j.virusres.2015.05.006

[57] Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, et al. Safety and efficacy of a recombinant hepatitis E vaccine. The New England Journal of Medicine. 2007;**356**(9):895-903

[58] Zhu FC, Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: A large-scale, randomised, double-blind placebocontrolled, phase 3 trial. Lancet. 2010;**376**(9744):895-902. DOI: 10.1016/ S0140-6736(10)61030-6

[59] Zhang J, Zhang XF, Huang SJ, Wu T, Hu YM, Wang ZZ, et al. Long-term efficacy of a hepatitis E vaccine. The New England Journal of Medicine. 2015;**372**(10):914-922. DOI: 10.1056/ NEJMoa1406011

[60] Galvez-Romero G, Salas-Rojas M, Pompa-Mera EN, Chávez-Rueda K, Aguilar-Setién Á. Addition of C3d-P28 adjuvant to a rabies DNA vaccine encoding the G5 linear epitope enhances the humoral immune response and confers protection. Vaccine. 2018;**36**(2):292-298. DOI: 10.1016/j.vaccine.2017.11.047

[61] Deshmukh TM, Lole KS, Tripathy AS, Arankalle VA. Immunogenicity of candidate hepatitis E virus DNA vaccine expressing complete and truncated ORF2 in mice. Vaccine. 2007;**25**(22):4350-4360

[62] Renoux VM, Fleury MJ, Bousarghin L, Gaitan J, Sizaret PY, Touzé A, et al. Induction of antibody response against hepatitis E virus (HEV) with recombinant human papillomavirus pseudoviruses expressing truncated HEV capsid proteins in mice. Vaccine. 2008;**26**(51):6602-6607. DOI: 10.1016/j. vaccine.2008.09.035

[63] Arankalle VA, Lole KS, Deshmukh TM, Srivastava S, Shaligram US. Challenge studies in rhesus monkeys immunized with candidate hepatitis E vaccines: DNA, DNA-prime-proteinboost and DNA-protein encapsulated in liposomes. Vaccine. 2009;**27**(7):1032- 1039. DOI: 10.1016/j.vaccine.2008.11.097

[64] Huang WJ, Zhang HY, Harrison TJ, Lan HY, Huang GY, Wang YC. Immunogenicity and protective efficacy in rhesus monkeys of a recombinant ORF2 protein from hepatitis E virus genotype 4. Archives of Virology. 2009;**154**(3):481-488. DOI: 10.1007/ s00705-009-0335-7

[65] Gilbert A, Johnson S, Walker N, Wickham C, Beath A, VerCauteren K. Efficacy of Ontario rabies vaccine baits (ONRAB) against rabies infection in raccoons. Vaccine. 2018;**36**(32 Pt B):4919- 4926. DOI: 10.1016/j.vaccine.2018.06.052

[66] Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1952;**46**(5):509-520

[67] World Health Organization (WHO) (2016) Report Zika Situation Neurological Syndrome and Congenital Anomalies. Available from: http:// www.who.int/emergencies/zika-virus/ situation-report/5-february-2016/en/

[68] Vorou R. Zika virus, vectors, reservoirs, amplifying hosts, and their potential to spread worldwide: What we know and what we should investigate urgently. International Journal of Infectious Diseases. 2016;**48**:85-90. DOI: 10.1016/j.ijid.2016.05.014

[69] Shepherd RC, Williams MC. Studies on viruses in east African bats (Chiroptera). 1. Haemagglutination inhibition and circulation of arboviruses. Zoonoses Research. 1964;**3**(3):125-139

[70] Simpson DI, Williams MC, O'Sullivan JP, Cunningham JC, Mutere FA. Studies on arboviruses and bats (Chiroptera) in East Africa. II. Isolation and haemagglutination-inhibition studies on bats collected in Kenya and throughout Uganda. Annals of Tropical Medicine and Parasitology. 1968;**62**(4):432-440

[71] Calisher CH, Childs JE, Field HE, Holmes KV, Schountz T. Bats: Important reservoir hosts of emerging viruses. Clinical Microbiology Reviews. 2006;**19**(3):531-545

[72] Bittar C, Machado RRG, Comelis MT, Bueno LM, Morielle-Versute E, Beguelini MR, et al. Lack of serological and molecular evidence of arbovirus infections in bats from Brazil. PLoS One. 2018;**13**(11):e0207010. DOI: 10.1371/journal.pone.0207010

[73] Garg H, Mehmetoglu-Gurbuz T, Joshi A. Recent advances in Zika virus vaccines. Viruses. 2018;**10**(11):E631. DOI: 10.3390/v10110631

**55**

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future…*

*DOI: http://dx.doi.org/10.5772/intechopen.84765*

[75] Rewar S, Mirdha D. Transmission of Ebola virus disease: An overview. Annals of Global Health. 2014;**80**(6):444-451. DOI: 10.1016/j.aogh.2015.02.005

[76] Zhou P, Chionh YT, Irac SE, Ahn M, Jia Ng JH, Fossum E, et al. Unlocking bat immunology: Establishment of *Pteropus alecto* bone marrow-derived dendritic cells and macrophages. Scientific Reports. 2016;**6**:38597. DOI: 10.1038/

[77] Marzi A, Mire CE. Current Ebola virus vaccine progress. BioDrugs. 2019. In press. DOI: 10.1007/

[78] Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats and coronaviruses. Viruses. 2019;**11**(1):E41.

[74] Beck C, Jimenez-Clavero MA, Leblond A, Durand B, Nowotny N, Leparc-Goffart I, et al. Flaviviruses in Europe: Complex circulation patterns and their consequences for the diagnosis and control of West Nile disease. International Journal of Environmental Research and Public Health. 2013;**10**(11):6049-6083. DOI:

10.3390/ijerph10116049

srep38597

s40259-018-0329-7

DOI: 10.3390/v11010041

virusres.2007.03.012

[79] Shi Z, Hu Z. A review of studies on animal reservoirs of the SARS coronavirus. Virus Research. 2008;**33**(1):74-87. DOI: 10.1016/j.

*Vaccines Targeted to Zoonotic Viral Infections in the Wildlife: Potentials, Limitations, and Future… DOI: http://dx.doi.org/10.5772/intechopen.84765*

[74] Beck C, Jimenez-Clavero MA, Leblond A, Durand B, Nowotny N, Leparc-Goffart I, et al. Flaviviruses in Europe: Complex circulation patterns and their consequences for the diagnosis and control of West Nile disease. International Journal of Environmental Research and Public Health. 2013;**10**(11):6049-6083. DOI: 10.3390/ijerph10116049

*Vaccines - The History and Future*

[60] Galvez-Romero G, Salas-Rojas M, Pompa-Mera EN, Chávez-Rueda K, Aguilar-Setién Á. Addition of C3d-P28 adjuvant to a rabies DNA vaccine encoding specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1952;**46**(5):509-520

[67] World Health Organization (WHO) (2016) Report Zika Situation Neurological Syndrome and Congenital Anomalies. Available from: http:// www.who.int/emergencies/zika-virus/ situation-report/5-february-2016/en/

[68] Vorou R. Zika virus, vectors, reservoirs, amplifying hosts, and their potential to spread worldwide: What we know and what we should investigate urgently. International Journal of Infectious Diseases. 2016;**48**:85-90. DOI: 10.1016/j.ijid.2016.05.014

[69] Shepherd RC, Williams MC. Studies

on viruses in east African bats (Chiroptera). 1. Haemagglutination inhibition and circulation of arboviruses. Zoonoses Research. 1964;**3**(3):125-139

[70] Simpson DI, Williams MC, O'Sullivan JP, Cunningham JC, Mutere FA. Studies on arboviruses and bats (Chiroptera) in East Africa. II. Isolation and haemagglutination-inhibition studies on bats collected in Kenya and throughout Uganda. Annals of Tropical Medicine and Parasitology.

[71] Calisher CH, Childs JE, Field HE, Holmes KV, Schountz T. Bats: Important reservoir hosts of emerging viruses. Clinical Microbiology Reviews.

[72] Bittar C, Machado RRG, Comelis MT, Bueno LM, Morielle-Versute E, Beguelini MR, et al. Lack of serological and molecular evidence of arbovirus infections in bats from Brazil. PLoS One. 2018;**13**(11):e0207010. DOI: 10.1371/journal.pone.0207010

[73] Garg H, Mehmetoglu-Gurbuz T, Joshi A. Recent advances in Zika virus vaccines. Viruses. 2018;**10**(11):E631.

DOI: 10.3390/v10110631

1968;**62**(4):432-440

2006;**19**(3):531-545

the G5 linear epitope enhances the humoral immune response and confers protection. Vaccine. 2018;**36**(2):292-298. DOI: 10.1016/j.vaccine.2017.11.047

2007;**25**(22):4350-4360

vaccine.2008.09.035

[61] Deshmukh TM, Lole KS, Tripathy AS, Arankalle VA. Immunogenicity of candidate hepatitis E virus DNA vaccine expressing complete and truncated ORF2 in mice. Vaccine.

[62] Renoux VM, Fleury MJ, Bousarghin

[63] Arankalle VA, Lole KS, Deshmukh TM, Srivastava S, Shaligram US. Challenge studies in rhesus monkeys immunized with candidate hepatitis E vaccines: DNA, DNA-prime-proteinboost and DNA-protein encapsulated in liposomes. Vaccine. 2009;**27**(7):1032- 1039. DOI: 10.1016/j.vaccine.2008.11.097

[64] Huang WJ, Zhang HY, Harrison TJ,

Immunogenicity and protective efficacy in rhesus monkeys of a recombinant ORF2 protein from hepatitis E virus genotype 4. Archives of Virology. 2009;**154**(3):481-488. DOI: 10.1007/

Lan HY, Huang GY, Wang YC.

[65] Gilbert A, Johnson S, Walker N, Wickham C, Beath A, VerCauteren K. Efficacy of Ontario rabies vaccine baits (ONRAB) against rabies infection in raccoons. Vaccine. 2018;**36**(32 Pt B):4919- 4926. DOI: 10.1016/j.vaccine.2018.06.052

[66] Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological

s00705-009-0335-7

L, Gaitan J, Sizaret PY, Touzé A, et al. Induction of antibody response against hepatitis E virus (HEV) with recombinant human papillomavirus pseudoviruses expressing truncated HEV capsid proteins in mice. Vaccine. 2008;**26**(51):6602-6607. DOI: 10.1016/j.

**54**

[75] Rewar S, Mirdha D. Transmission of Ebola virus disease: An overview. Annals of Global Health. 2014;**80**(6):444-451. DOI: 10.1016/j.aogh.2015.02.005

[76] Zhou P, Chionh YT, Irac SE, Ahn M, Jia Ng JH, Fossum E, et al. Unlocking bat immunology: Establishment of *Pteropus alecto* bone marrow-derived dendritic cells and macrophages. Scientific Reports. 2016;**6**:38597. DOI: 10.1038/ srep38597

[77] Marzi A, Mire CE. Current Ebola virus vaccine progress. BioDrugs. 2019. In press. DOI: 10.1007/ s40259-018-0329-7

[78] Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats and coronaviruses. Viruses. 2019;**11**(1):E41. DOI: 10.3390/v11010041

[79] Shi Z, Hu Z. A review of studies on animal reservoirs of the SARS coronavirus. Virus Research. 2008;**33**(1):74-87. DOI: 10.1016/j. virusres.2007.03.012

**57**

Section 5

GMO-based Vaccines and

their Regulatory Affairs

Section 5
