Review of Medical Microbiology and Immunology, 13th Edition

36. Viral Vaccines

CHAPTER CONTENTS

Introduction

Active Immunity

Passive Immunity

Herd Immunity

Pearls

Self-Assessment Questions

Practice Questions: USMLE & Course Examinations

Because few drugs are useful against viral infections, prevention of infection by the use of vaccines is very important. Prevention of viral diseases can be achieved by the use of vaccines that induce active immunity or by the administration of preformed antibody that provides passive immunity.

There are two types of vaccines that induce active immunity: those that contain live virus whose pathogenicity has been attenuated¹ and those that contain killed virus. Some vaccines, such as the hepatitis B vaccine, contain purified viral proteins and are often called subunit vaccines. The features of subunit vaccines resemble those of killed vaccines because no viral replication occurs in these vaccines. The attributes of live and killed vaccines are listed in Table 36–1.

TABLE 36–1 Characteristics of Live and Killed Viral Vaccines

In general, live vaccines are preferred to vaccines containing killed virus because their protection is greater and longer-lasting. With live vaccines, the virus multiplies in the host, producing a prolonged antigenic stimulus, and IgA and IgG are elicited when the vaccine is administered by the natural route of infection (e.g., when polio vaccine is given orally). Killed vaccines, which are usually given intramuscularly, do not stimulate a major IgA response. Killed vaccines typically do not stimulate a cytotoxic T-cell response, because the virus in the vaccine does not replicate. In the absence of replication, no viral epitopes are presented in association with class I MHC proteins, and the cytotoxic T-cell response is not activated (see Chapter 58). Although live vaccines stimulate a long-lasting response, booster doses are now recommended with measles and polio vaccines.

One unique form of a live, attenuated viral vaccine is the influenza vaccine that contains a temperature-sensitive mutant of the virus as the immunogen. The temperature-sensitive mutant will replicate in the cooler air passages of the nose, where it induces IgA-based immunity, whereas it will not replicate in the warmer lung tissue and therefore will not cause disease.

There are three concerns about the use of live vaccines:

(1) They are composed of attenuated viral mutants, which can revert to virulence either during vaccine production or in the immunized person. Reversion to virulence during production can be detected by quality control testing, but there is no test to predict whether reversion will occur in the immunized individual. Of the commonly used live vaccines, only polio vaccine has had problems regarding revertants; measles, mumps, rubella, and varicella vaccines have not.

Even if the virus in the live vaccine does not revert, it can still cause disease because, although attenuated (weakened), it can still be pathogenic in a host with reduced immunity. For this reason, live viral vaccines should not be given to immunocompromised people or to pregnant women because the fetus may become infected.

(2) The live vaccine can be excreted by the immunized person. This is a double-edged sword. It is advantageous if the spread of the virus successfully immunizes others, as occurs with the live polio vaccine. However, it could be a problem if, for example, a virulent poliovirus revertant spreads to a susceptible person. Rare cases of paralytic polio occur in the United States each year by this route of infection.

(3) A second virus could contaminate the vaccine if it was present in the cell cultures used to prepare the vaccine. This concern exists for both live and killed vaccines, although, clearly, the live vaccine presents a greater problem, because the process that inactivates the virus in the killed vaccine could inactivate the contaminant as well. It is interesting, therefore, that the most striking incidence of contamination of a vaccine occurred with the killed polio vaccine. In 1960, it was reported that live simian vacuolating virus 40 (SV40 virus), an inapparent “passenger” virus in monkey kidney cells, had contaminated some lots of polio vaccine and was resistant to the formaldehyde used to inactivate the poliovirus. There was great concern when it was found that SV40 virus causes sarcomas in a variety of rodents. Fortunately, it has not caused cancer in the individuals inoculated with the contaminated polio vaccine.

Certain viral vaccines, namely, influenza, measles, mumps, and yellow fever vaccines, are grown in chick embryos. These vaccines should not be given to those who have had an anaphylactic reaction to eggs. People with allergies to chicken feathers can be immunized.

In addition to the disadvantages of the killed vaccines already mentioned—namely, that they induce a shorter duration of protection, are less protective, and induce fewer IgA antibodies—there is the potential problem that the inactivation process might be inadequate. Although this is rare, it happened in the early days of the manufacture of the killed polio vaccine. However, killed vaccines do have two advantages: They cannot revert to virulence, and they are more heat-stable. Therefore, they can be used more easily in tropical climates.

Most viral vaccines are usually given before a known exposure (i.e., they are administered preexposure). However, there are two vaccines, the vaccines against rabies and hepatitis B, that are also effective when given postexposure because the incubation period of these diseases is long enough that the vaccine-induced immunity can prevent the disease. Thus the rabies vaccine is most often used in people after they have received a bite from a potentially rabid animal, and the hepatitis B vaccine is used in people who have sustained a needle-stick injury.

The prospect for the future is that some of the disadvantages of current vaccines will be bypassed by the use of purified viral antigens produced from genes cloned in either bacteria or yeasts. The advantages of antigens produced by the cloning process are that they contain no viral nucleic acid and so cannot replicate or revert to virulence, they have no contaminating viruses from cell culture, and they can be produced in large amounts. A disadvantage of these cloned vaccines is that they are unlikely to stimulate a cytotoxic T-cell response because no viral replication occurs.

Another prospect for the future is the use of “DNA vaccines.” These vaccines contain purified DNA encoding the appropriate viral proteins genetically engineered into a viral vector or plasmid. Immunization with this composite DNA elicits both antibody and cytotoxic T cells and protects against disease in experimental animals.

Certain live viral vaccines, such as the vaccines containing vaccinia virus, adenovirus, and poliovirus, are being used experimentally to immunize against other viruses such as HIV. This is done by splicing the HIV gene into the live viral genome and then infecting the experimental animal with the constructed virus. The advantage of this procedure is that a cytotoxic T-cell response is elicited (because the virus is replicating), whereas if the purified antigen alone were used to immunize the animal, an antibody response but not a cytotoxic T-cell response would be elicited.

The viral vaccines currently in use are described in Table 36–2. The vaccines, both viral and bacterial, recommended for children from 0 to 6 years of age are listed in Table 36–3.

TABLE 36–2 Current Viral Vaccines

TABLE 36–3 Vaccines Recommended for Children Aged 0–6 Years^1,2

Passive immunity is provided by the administration of preformed antibody in preparations called immune globulins. The immune globulins useful in the prevention of viral diseases are described next. Passive–active immunity is induced by giving both immune globulins to provide immediate protection and a vaccine to provide long-term protection. This approach is described in the sections on rabies and hepatitis B. The following preparations are available:

(1) Rabies immune globulin (RIG) is used in the prevention of rabies in people who may have been exposed to the virus. It is administered by injecting as much RIG as possible into the tissue at the bite site, and the remainder is given intramuscularly. The preparation contains a high titer of antibody made by hyperimmunizing human volunteers with rabies vaccine. RIG is obtained from humans to avoid hypersensitivity reactions. In addition to RIG, the vaccine containing killed rabies virus made in human diploid cells should be given. RIG and the vaccine should be given at different sites. This is an example of passive–active immunization.

(2) Hepatitis B immune globulin (HBIG) is used in the prevention of hepatitis B in people who may have been exposed to the virus either by needle-stick or as a neonate born of a mother who is a carrier of hepatitis B virus. The preparation contains a high titer of antibody to hepatitis B virus and is obtained from humans to avoid hypersensitivity reactions. HBIG is often used in conjunction with hepatitis B vaccine, an example of passive–active immunization.

(3) Varicella-zoster immune globulin (VZIG) is used in the prevention of disseminated zoster in people who may have been exposed to the virus and who are immunocompromised. The preparation contains a high titer of antibody to varicella-zoster virus and is obtained from humans to avoid hypersensitivity reactions.

(4) Vaccinia immune globulins (VIG) can be used to treat some of the complications of the smallpox vaccination.

(5) Immune globulins (IGs) are useful in the prevention (or mitigation) of hepatitis A or measles in people who may have been exposed to these viruses. IGs are commonly used prior to traveling to areas of the world where hepatitis A virus is endemic. IGs contain pooled serum obtained from a large number of human volunteers who have not been hyperimmunized. The effectiveness of IG is based on antibody being present in many members of the pool.

Herd immunity (also known as community immunity) occurs when a sufficiently large percentage of the population (the “herd”) is immunized so that an unimmunized individual is protected (see Chapter 33). For herd immunity to occur, the vaccine must prevent transmission of the virus as well as prevent disease. For example, the live, attenuated polio vaccine can provide good herd immunity because it induces intestinal IgA, which prevents poliovirus from replicating in the gastrointestinal tract and being transmitted to others. However, the killed polio vaccine does not induce herd immunity because secretory IgA is not produced, and immunized individuals (although protected from poliomyelitis) can still serve as a source of poliovirus for others.

PEARLS

Active Immunity

• Active immunity can be elicited by vaccines containing killed viruses, purified protein subunits, or live, attenuated (weakened) viruses.

• In general, live viral vaccines are preferable to killed vaccines for three reasons: (1) they induce a higher titer of antibody and hence longer-lasting protection; (2) they induce a broader range of antibody (e.g., both IgA and IgG, not just IgG); and (3) they activate cytotoxic T cells, which kill virus-infected cells.

• There are some potential problems with live viral vaccines, the most important of which is reversion to virulence. Transmission of the vaccine virus to others who may be immunocompromised is another concern. Also there may be a second, unwanted virus in the vaccine that was present in the cells used to make the vaccine virus. This second virus may cause adverse effects.

• Live viral vaccines should not be given to immunocompromised individuals or to pregnant women.

• Vaccines grown in chick embryos, especially influenza vaccine, should not be given to those who have had an anaphylactic reaction to eggs.

Passive Immunity

• Passive immunity is immunity acquired by an individual by the transfer of preformed antibodies made in either other humans or in animals. These antibody preparations are often called immune globulins. Passive immunity also occurs naturally when IgG is transferred from the mother to the fetus across the placenta and when IgA is transferred from the mother to the newborn in colostrum.

• The main advantage of passive immunity is that it provides immediate protection. The main disadvantage is that it does not provide long-term protection (i.e., it is active only for a few weeks to a few months).

• Immune globulin preparations against rabies virus, hepatitis A virus, hepatitis B virus, and varicella-zoster virus are effective.

• Passive–active immunity consists of administering both immune globulins and a viral vaccine. This provides both immediate as well as long-term protection. For example, protection against rabies in an unimmunized person who has been bitten by a potentially rabid animal consists of both rabies immune globulins and the rabies vaccine.

Herd Immunity

• Herd immunity is the protection of an individual that results from immunity in many other members of the population (the “herd”) that interrupts transmission of the virus to the individual. Herd immunity can be achieved either by active immunization or by natural infection of a sufficiently high percentage of the population. Herd immunity is unlikely to be achieved by passive immunity because, although antibodies can protect the individual against spread of virus through the bloodstream, they are unlikely to prevent viral replication at the portal of entry and consequent transmission to others.

1. Regarding viral vaccines, which one of the following is the MOST accurate?

(A) Killed vaccines induce a longer lasting response than do live, attenuated vaccines.

(B) Killed vaccines are no longer used in this country because they do not induce secretory IgA.

(C) Killed vaccines induce a broader range of immune responses than do live, attenuated vaccines.

(D) Killed vaccines are safer to give to immunocompromised patients than are live, attenuated vaccines.

2. Individuals who have had an anaphylactic reaction to egg proteins should NOT receive which one of the following vaccines?

(A) Hepatitis A vaccine

(B) Hepatitis B vaccine

(C) Influenza vaccine

(D) Polio vaccine

(E) Rabies vaccine

3. Induction of passive–active immunity is useful in the prevention of which one of the following sets of two viral diseases?

(A) Hepatitis A and dengue

(B) Hepatitis B and rabies

(C) Influenza and varicella

(D) Mumps and yellow fever

(E) Rubella and measles

4. Protection of the unimmunized individual based on immunization of a sufficient number of other members of the population is a description of which one of the following?

(A) Active immunity

(B) Herd immunity

(C) Passive immunity

(D) Passive–active immunity

(E) Postexposure immunity

1. (D)

2. (C)

3. (B)

4. (B)

Questions on the topics discussed in this chapter can be found in the Basic Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 700. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

¹ An attenuated virus is one that is unable to cause disease, but retains its antigenicity and can induce protection.

PART IV CLINICAL VIROLOGY

Most of the clinically important viral pathogens can be categorized into groups according to their structural characteristics (i.e., DNA enveloped viruses, DNA nonenveloped¹ viruses, RNA enveloped viruses, and RNA nonenveloped viruses) (see Chapters 37–40 and Table IV–1).

TABLE IV–1 Major Viral Pathogens

However, some viruses (e.g., arboviruses, tumor viruses, and slow viruses) (see Chapters 41–45) are described best in terms of their biologic features. Several clinically less prominent viruses (e.g., parvoviruses and coronaviruses) are described in Chapter 46. An overview of the viruses in the four structural categories follows.

Herpesviruses

These viruses are noted for their ability to cause latent infections. This family includes (1) herpes simplex virus types 1 and 2, which cause painful vesicles on the face and genitals, respectively; (2) varicella-zoster virus, which causes varicella (chickenpox) typically in children and, when it recurs, zoster (shingles); (3) cytomegalovirus, an important cause of congenital malformations; (4) Epstein–Barr virus, which causes infectious mononucleosis; and (5) human herpesvirus 8, which causes Kaposi’s sarcoma. (See Chapter 37.)

Hepatitis B Virus

This virus is one of the important causes of viral hepatitis. In contrast to hepatitis A virus (an RNA nucleocapsid virus), hepatitis B virus causes a more severe form of hepatitis, results more frequently in a chronic carrier state, and is implicated in the induction of hepatocellular carcinoma, the most common cancer worldwide. (See Chapter 41.)

Poxviruses

Poxviruses are the largest and most complex of the viruses. The disease smallpox has been eradicated by effective use of the vaccine. Molluscum contagiosum virus is the only poxvirus that causes human disease in the United States at this time. (See Chapter 37.)

Adenoviruses

These viruses are best known for causing upper and lower respiratory tract infections, including pharyngitis and pneumonia. (See Chapter 38.)

Papillomaviruses

These viruses cause papillomas on the skin and mucous membranes of many areas of the body. Some types are implicated as a cause of cancer (e.g., carcinoma of the cervix). (See Chapter 38.)

Parvovirus B19

This virus causes “slapped cheeks” syndrome, hydrops fetalis, and severe anemia, especially in those with hereditary anemias such as sickle cell anemia. (See Chapter 38.)

Respiratory Viruses

(1) Influenza A and B viruses. Influenza A virus is the major cause of recurrent epidemics of influenza.

(2) Parainfluenza viruses. These viruses are the leading cause of croup in young children and an important cause of common colds in adults.

(3) Respiratory syncytial virus. This virus is the leading cause of bronchiolitis and pneumonia in infants. (See Chapter 39.)

Measles, Mumps, and Rubella Viruses

These viruses cause well-known childhood diseases and are the viral components of the MMR vaccine. Widespread use of the vaccine has markedly reduced the incidence of these diseases in the United States. These viruses are well known for the complications associated with the diseases they cause (e.g., rubella virus infection in a pregnant woman can cause congenital malformations). (See Chapter 39.)

Rabies Virus

This virus causes almost invariably fatal encephalitis following the bite of a rabid animal. In the United States, wild animals such as skunks, foxes, raccoons, and bats are the major sources, but human infection is rare. (See Chapter 39.)

Hepatitis C Virus

This virus causes hepatitis C, the most prevalent form of viral hepatitis in the United States. It causes a very high rate of chronic carriers and predisposes to chronic hepatitis and hepatic carcinoma.

Human T-Cell Lymphotropic Virus

This virus causes T-cell leukemia in humans. It also causes an autoimmune disease called tropical spastic paraparesis. (See Chapter 43.)

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). (See Chapter 45.)

Enteroviruses

These viruses infect the enteric tract and are transmitted by the fecal–oral route. Poliovirus rarely causes disease in the United States because of the vaccine but remains an important cause of aseptic meningitis and paralysis in developing countries. Of more importance in the United States are Coxsackie viruses, which cause aseptic meningitis, myocarditis, and pleurodynia; and echoviruses, which cause aseptic meningitis. (See Chapter 40.)

Rhinoviruses

These viruses are the most common cause of the common cold. They have a large number of antigenic types, which may account for their ability to cause disease so frequently. (See Chapter 40.)

Rotaviruses

These viruses possess an unusual genome composed of double-stranded RNA in 11 segments. Rotaviruses are an important cause of viral gastroenteritis in young children. (See Chapter 40.)

Hepatitis A Virus

This virus is an important cause of hepatitis. It is an enterovirus but is described in this book in conjunction with hepatitis B virus. It is structurally different from hepatitis B virus, which is a DNA enveloped virus. Furthermore, it is epidemiologically distinct (i.e., it primarily affects children, is transmitted by the fecal–oral route, and rarely causes a prolonged carrier state). (See Chapter 41.)

Noroviruses

Noroviruses are a common cause of gastroenteritis, especially in adults. They are a well-known cause of outbreaks of vomiting and diarrhea in hospitals, nursing homes, and on cruise ships (see Chapter 40).

Hepeviruses

The main human pathogen in the hepevirus family is hepatitis E virus (HEV). It causes hepatitis acquired by fecal–oral transmission similar to hepatitis A virus. HEV is a nonenveloped virus with a positive-polarity single-stranded RNA genome.

Chapter 42 describes the large and varied group of arboviruses, which have the common feature of being transmitted by an arthropod. Chapter 43 covers tumor viruses, and Chapter 44 covers the “slow” viruses, which cause degenerative central nervous system diseases primarily. Chapter 45 describes HIV, the cause of AIDS. The less common viral pathogens are described in Chapter 46.

Table IV–2 lists the frequency of the 10 most common notifiable viral diseases in the United States for 2009 (the latest year for which complete data are available). Note that the common cold, which is probably the most frequent disease, is not listed because it is not a notifiable disease.

TABLE IV–2 The 10 Most Common Notifiable Viral Diseases in the United States in 2011¹

¹Nonenveloped viruses are also called naked nucleocapsid viruses.