Vaccines and Immunization Procedures

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A vaccine is a preparation of a disease-causing agent or its products used to induce active immunity. Vaccines not only protect an individual against disease, they can also prevent diseases from spreading in a population. When a critical portion of a population is immune to a disease, either through natural immunity or vaccination, a phenomenon called herd immunity develops.

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This is the inability of an infectious disease to spread because of the lack of a critical concentration of susceptible hosts. Herd immunity is responsible for dramatic declines in childhood diseases, both in the United States and in developing countries. Unfortunately, we periodically see some of these diseases reappear and spread as a direct consequence of parents failing to have their children vaccinated. Table 17.1 lists a number of human diseases for which vaccines are available. As the table indicates, some are routinely used, whereas others are employed only in special circumstances.

Table 17.1 Some Important Immunizing Agents for Humans

Disease

Type of Vaccine

Persons Who Should Receive the Vaccine

Anthrax

Acellular

People in occupations that put them at risk of exposure, such as military personnel

Diphtheria

Toxoid

Children; adults receive a booster every 10 years

Haemophilus influenzae type b infections

Polysaccharide-protein conjugate

Children

Hepatitis A

Inactivated virus

Children who live in selected regions, people traveling to certain parts of the world

Hepatitis B

Protein subunit is produced by genetically engineered Saccharomyces cereviseae and purified

Children, adults in high-risk groups such as IV drug abusers, health care workers who might be exposed to infected blood, and contacts of infected people, homosexual men, and people who have multiple sexual partners

Influenza

Inactivated virus, usually given by injection in the United States, but as a nasal spray in parts of Europe

Adults over age 50, medical personnel, and people at increased risk for complications; given yearly, as the antigens of the virus change frequently

Measles

Attenuated virus

Children, people entering college, adults born after 1956 who have not been immunized, travelers to foreign countries, and HIV-infected people without severe immunosuppression

Meningococcal disease

Purified polysaccharide (4 serotypes)

Children and adults with certain conditions that put them at greater risk (for example, those without a spleen or who have certain complement system defects); people traveling to sub-Saharan Africa

Mumps

Attenuated virus

Same as measles

Pertussis (whooping cough)

Acellular vaccine given together with diphtheria and tetanus toxoids (DTaP)

Children

Pneumococcal infection

Two forms—purified polysaccharide (PPV) and polysaccharide-protein conjugate (PCV)

Children should receive PCV; adults over 65, people with certain chronic infections, and others in high-risk groups should receive PPV

Rabies

Inactivated virus grown in human or rhesus monkey cells

People exposed to the virus, people at high risk for exposure, such as veterinarians and other animal handlers

Rubella (German measles)

Attenuated virus

Children, adults (particularly women) who are susceptible, health care workers who are at high risk of exposure

Tetanus

Toxoid

Children; adults receive a booster every 10 years

Tuberculosis

Attenuated BCG strain of tuberculosis bacteria

Used only in special circumstances in the United States; widely used in other countries

Typhoid fever

Two forms—attenuated bacteria (taken orally) and purified polysaccharide

People traveling to certain parts of the world

Varicella-zoster (chickenpox)

Attenuated virus

Children; may also be given to susceptible adults

Yellow fever

Attenuated virus

Travelers to affected areas

422 Chapter 17 Applications of Immune Responses

Table 17.2 A Comparison of Characteristics of Attenuated and Inactivated Vaccines

Characteristic

Attenuated Vaccine

Inactivated Vaccine

Antibody response

IgG; IgA if administered orally

IgG

Cellular immune response

Good

Poor

Duration of protection

Long-term

Short-term

Need for adjuvant

No

Yes

Number of doses

Usually single

Multiple

Risk of mutation to virulence

Very low

Absent

Route of administration

Injection or oral

Injection

Stability in warm temperatures

Poor

Good

Types

Attenuated viruses, attenuated bacteria

Inactivated whole agents, toxoids, subunit vaccines, polysaccharide vaccines

Effective vaccines should be safe, with few side effects, while giving lasting protection against the specific illness. They should induce specific antibodies or immune cells, or both, as appropriate. For example, polio vaccine should induce antibodies that neutralize the virus, thus preventing it from reaching and attaching to nerve cells to cause the paralysis of severe poliomyelitis. On the other hand, an effective vaccine against tuberculosis would induce cellular immunity that can limit growth of the intracellular bacteria. Of course, vaccines ideally should be low in cost, stable with a long shelf life, and easy to administer.

Vaccines fall into two general categories, attenuated and inactivated, based on whether or not the immunizing agent can replicate. Each type has characteristic advantages and disadvantages (table 17.2).

Attenuated Vaccines

An attenuated vaccine is a weakened form of the disease -causing microorganism or virus that is generally unable to cause disease. The attenuated strain replicates in the vaccine recipient, causing an infection with undetectable or mild disease that typically results in long-lasting immunity. Because infection with the attenuated strain mimics that of the wild-type strain, the type of immunity it evokes is generally appropriate for controlling the infection. For example, those that are given orally induce mucosal immunity (an IgA response), protecting against disease-causing agents that infect via the gastrointestinal tract. Some attenuated vaccines are able to stimulate T-cytotoxic cells, inducing cellular immunity.

Production of an attenuated strain often involves successively culturing the microbe under a given set of conditions, resulting in a gradual accumulation of mutations that make it less able to cause disease. Pasteur first produced successful vaccines of attenuated anthrax and chicken cholera by growing the organisms at higher than normal temperatures and in other unusual conditions. Viruses of humans may be attenuated by growing them in cells of a different animal species; mutations occur so that the virus then grows poorly in human cells. Genetic manipulation is now being used to produce strains of pathogens with low virulence. Specific genes are mutated and used to replace wild-type genes. The inserted mutant genes are engineered so they cannot revert to the wild type. Also, genes can be deleted from vaccine virus strains, making them safer and giving the added advantage of being able to trace the virus and distinguish it from wild strains.

Attenuated vaccines have several characteristics that may make them more desirable than their inactivated counterparts. For example, a single dose of an attenuated agent can be sufficient to induce long-lasting immunity. This is because the microbe multiplies in the body, causing the immune system to be exposed to the antigen for a longer period and in greater amounts than with inactivated agents. In addition, the vaccine strain has the added potential of being spread from an individual being immunized to other non-immune people, inadvertently immunizing the contacts of the vaccine recipient.

The disadvantage of using attenuated agents to immunize is that they have the potential to cause disease in immunosup-pressed people, and rarely they can revert or mutate to strains that cause serious disease. Care must be taken to avoid giving attenuated vaccines to pregnant women, because the microbes may cross the placenta and cause damage to the developing fetus. Another disadvantage of attenuated vaccines, especially in developing countries where they are desperately needed, is that they usually require refrigeration to keep them active. Attenuated vaccines currently in widespread use include those against measles, mumps, rubella, and yellow fever. The Sabin vaccine against polio is also an attenuated vaccine.

Inactivated Vaccines

An inactivated vaccine is unable to replicate, but retains the immunogenicity of the infectious agent or toxin. Inactivated vaccines fall into two general categories—whole agents and fractions of the agent.

The advantage of inactivated vaccines is that they cannot cause infections or revert to dangerous forms. Because they do not replicate, however, the magnitude of the immune response is limited because there is no amplification of the dose in vivo. To compensate for the relatively low effective dose, it is usually necessary to give several booster doses of the vaccine to induce protective immunity.

Inactivated whole agent vaccines contain killed microorganisms or inactivated viruses. The vaccines are made by treating the infectious agent with a chemical such as formalin, which does not significantly change the surface epitopes. Such treatments leave the agent antigenic even though it cannot reproduce. Inactivated whole agent vaccines include those against cholera, plague, influenza, rabies, and the Salk vaccine against polio. ■ formalin, p. 118

Toxoids are inactivated toxins used to protect against diseases that are due to production of a toxin by the invading bacterium. They are prepared by treating the toxins to destroy the toxic part of the molecules while retaining the antigenic epitopes. Diphtheria and tetanus vaccines are toxoids. An initial series of doses are given in childhood, followed by booster vaccines every 10 years.

Protein subunit vaccines are composed of key protein antigens or antigenic fragments of an infectious agent, rather than whole cells or viruses. Obviously, they can only be developed after research has revealed which of the components of the microbe are most important in eliciting a protective immune response. Their advantage is that parts of the microbe that sometimes cause undesirable side effects are not included. For example, the whooping cough (pertussis) killed vaccine that was previously used routinely for immunizing babies and young children often caused reactions such as pain, tenderness at the site of the injection, fever, and occasionally, convulsions. A subunit vaccine, referred to as the acellular pertussis (aP) vaccine, does not cause these side effects and has now replaced the killed whole cell vaccine. A recombinant vaccine is a subunit vaccine produced by a genetically engineered microorganism. An example is the vaccine against the hepatitis B virus; it is produced by yeast cells that have been engineered to produce part of the viral protein coat.

Polysaccharide vaccines are composed of the polysaccharides that make up the capsule of certain organisms. Recall that polysaccharides are T-independent antigens; they generally elicit only an IgM response, provide no memory, and elicit a poor response in young children. Conjugate vaccines represent an improvement over purified polysaccharide vaccines because they are effective in young children. Developers intentionally converted polysaccharides into T-dependent antigens by chemically linking the polysaccharides to proteins. The first conjugate vaccine developed was against Haemophilus influenzae type b; it has nearly eliminated meningitis caused by this organism in children. The conjugate vaccine recently developed against certain Streptococcus pneumoniae strains promises to do the same for a variety of infections caused by those strains. ■ Haemophilus influenzae type b, p. 666 ■ Streptococcus pneumoniae, p. 576

17.2 Vaccines and Immunization Procedures 423

Many inactivated vaccines contain an adjuvant, a substance that enhances the immune response to antigens. These are necessary additives because purified antigens such as toxoids and subunit vaccines are often poorly immunogenic by themselves because they lack the "danger" signals, the patterns associated with tissue damage or invading microbes. These patterns trigger dendritic cells to produce co-stimulatory molecules, allowing them to activate T-helper cells, which, in turn, activate B cells. Adjuvants are thought to function by providing the "danger" signals to dendritic cells. Some adjuvants appear to adsorb the antigen, releasing it at a slow but constant rate to the tissues and surrounding blood vessels. Unfortunately, many effective adjuvants evoke an intense inflammatory response, making them unsuitable for use in vaccines for humans. Currently, the only adjuvant approved in the United States for use in vaccines for humans is alum (aluminum hydroxide and aluminum phosphate), although several others are being tested in clinical trials. ■ pattern recognition, p. 372 ■ dendritic cells, pp. 378,410

An Example of Vaccination Strategy—The Campaign to Eliminate Poliomyelitis

Vaccines against poliomyelitis provide in excellent illustration of the complexity of vaccination strategies. The virus that causes this disease enters the body orally, infects the throat and intestinal tract, and then invades the bloodstream. From there, it may invade nerve cells and cause the disease poliomyelitis (see figure

26.17). There are three types of poliovirus, any of which can cause poliomyelitis. The Salk vaccine, developed in the mid-1950s, consists of inactivated viruses of all three types. It was a huge success in lowering the rate of the disease, but it had the disadvantage of requiring a series of injections over a period of time for maximum protection. In 1961, the Sabin vaccine became available, with the advantage of cheaper oral administration. Even though this attenuated poliovirus vaccine replicates in the intestine, however, it still has to be given in a series of three doses rather than one because of interactions among the three types of virus included in the vaccine. Both attenuated and inactivated polio vaccines induce circulating antibodies and protect against viral invasion of the central nervous system and consequent paralytic poliomyelitis. The Sabin vaccine has a distinct advantage over the Salk vaccine in that it induces mucosal immunity, and thus potentially provides herd immunity. ■ poliomyelitis, p. 677

Polio vaccination was so successful that by 1980 the United States was free of wild-type poliovirus (see figure

26.18). Ironically, poliomyelitis still occurred occasionally, caused by the vaccine strain; approximately one case of poliomyelitis arises for every 2.4 million doses of Sabin vaccine administered. An obvious way to avoid these vaccine-related illnesses is to abandon the Sabin vaccine in favor of the Salk vaccine. As usual, however, the situation is not as simple as it might seem. The Sabin vaccine, unlike the Salk vaccine, prevents transmission of the wild-type virus should it ever be reintroduced to the population. If only the inactivated vaccine is given, the virus can still replicate in the gastrointestinal tract and be transmitted to others, rapidly spreading in a population. Eventually the virus

424 Chapter 17 Applications of Immune Responses

Table 17.3 The Effectiveness of Universal Immunization in the United States

Disease Cases per Year Before Immunization

Decrease After Immunization

Smallpox

48,164 (1900-1904)

100%

Diphtheria

175,885 (1920-1922)

Nearly 100%

Pertussis (whooping cough)

147,271 (1922-1925)

95.7%

Tetanus

1,314 (1922-1926)

97.4%

Paralytic poliomyelitis

16,316 (1951-1954)

100%

Measles

503,282 (1958-1962)

Nearly 100%

Mumps

152,209 (1968)

99.6%

Rubella (congenital syndrome)

823 (estimated)

99.4%

Haemophilus influenzae type b infections

20,000 (estimated)

99.7%

may infect individuals who are susceptible, potentially causing an outbreak of poliomyelitis.

A campaign to eliminate polio worldwide was so successful that by 1991, wild poliovirus had been eliminated from the western hemisphere. By 1997, the worldwide incidence of polio had decreased substantially, minimizing the risk that wild-type polio would be reintroduced into the United States. Because of the continued risk of vaccine-associated paralytic polio, a vaccine strategy that attempted to capture the best of both vaccines was adopted. Children first received doses of the Salk vaccine, protecting them from poliomyelitis; following these doses the Sabin vaccine was given, providing mucosal protection while also boosting immunity. In mid-1999 the routine use of the Sabin vaccine was discontinued altogether. Although the original goal of global eradication of polio by 2000 was not achieved as was hoped, efforts are currently under way to eliminate it by 2005. This effort has been interrupted by war in some countries, but it has been possible at times to arrange a cease-fire for National Immunization Days, to permit this vital public health program to continue.

The Importance of Routine Immunizations for Children

Before vaccination was available for common childhood diseases, thousands of children died or were left with permanent disability from these diseases. Table 17.3 illustrates how dramatically vaccination has decreased the occurrence of certain infectious diseases. Unfortunately, even now, nearly 20% of American children under age two are not fully immunized and many people in the United States become ill or even die every year from diseases that are readily prevented by vaccines.

One reason some children are not fully vaccinated is that parents have refused to have their children vaccinated, fearing the rare chance that immunization procedures might be harmful. Vaccines have, in these cases, become victims of their own success. They have been so effective at preventing diseases that people have been lulled into a false sense of security. Reports of adverse effects of vaccination have led some people to falsely believe that the risk of vaccination is greater than the risk of diseases. Although there is some risk associated with almost any medical procedure, there is no question that the benefits of routine immunizations greatly outweigh the very slight risks. Data show that a child with measles has a 1:2,000 chance of developing serious encephalitic involvement of the nervous system, compared with a 1:1,000,000 chance from measles vaccine. Between 1989 and 1991 measles immunization rates dropped 10% and an outbreak of 55,000 cases occurred, with 120 deaths. Now that immunization rates have increased again, measles outbreaks are rarely seen. The suggestion that the measles, mumps, and rubella (MMR) vaccine is associated with autism in young children, however, is again threatening the acceptance of immunization. Studies so far have not shown evidence of this association, but more work is under way to be sure. Routine immunization against pertussis (whooping cough) caused a marked decrease in its incidence in the United States and saved many lives. Because of some adverse reactions to the killed whole cell vaccine being used, however, many parents refused to allow their babies to get this vaccine. By 1990, this refusal of vaccination resulted in the highest incidence of pertussis cases in 20 years and the deaths of some children, mostly those under one year of age. Currently an acellular subunit pertussis vaccine is used, usually in combination with diphtheria and tetanus toxoids (DTaP). Several large-scale studies have shown the acellular pertussis vaccine to be more effective and have fewer side effects than the whole cell vaccine.

The recommendations of the U.S. Center for Disease Prevention and Control for childhood and adolescent immunizations are shown in table 17.4. Since children need a minimum of 15 separate injections to complete the 2002 recommended childhood immunization schedule from birth to six years, it is desirable that several vaccines be combined into a

17.2 Vaccines and Immunization Procedures 425

Table 17.4 Recommended Childhood Immunization Schedule in the United States (2002)

Vaccine

Birth

1 mo

2 mo

4 mo

6 mo

12 mo

15 mo

18 mo

24mo

4-6 yrs

11-12 yrs 13-18 yrs

Hepatitis B

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