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Arguably the most important practical application of immunological principles is vaccines. Vaccines are materials that are designed to be innocuous but that can elicit an immune response for the purpose of providing protection against a challenge with the virulent version of a pathogen (Figure 23-38). It is not always known why vaccines are as successful as they are, but in many cases, the ability to raise antibodies that can neutralize a pathogen (viruses) or that show microbicidal effects (bacteria) are good indicators of successful vaccination.

FIGURE 23-38 Time course of a viral infection. The initial antiviral response, seen when the number of infectious particles rises, includes activation of natural killer (NK) cells and production of type I interferons. These responses are part of the innate immune response. The production of antibodies and the activation of cytotoxic T cells (CTLs) follow, eventually clearing the infection. Re-exposure to the same virus leads to more rapid and more pronounced production of antibodies and to more rapid activation of cytotoxic T cells. A successful vaccine induces an immune response similar in some respects to that following initial exposure to a pathogen, but without causing significant symptoms of disease. If a vaccinated person is subsequently exposed to the same pathogen, the adaptive immune system is primed to respond quickly and strongly.

Several strategies can lead to a successful vaccine. Serial passage of a pathogen in tissue culture or from animal to animal often leads to attenuation, the molecular basis for which is not well understood. Vaccines may be composed of live attenuated variants of more virulent pathogens. The attenuated version of the pathogen causes a mild form of the disease or causes no symptoms at all. However, by recruiting all the component parts of the adaptive immune system, such live attenuated vaccines can elicit protective levels of antibodies. These antibody levels may wane with advancing age because the lymphocytes responsible for immunological memory may have a finite life span, so repeated immunizations (booster injections) are often required to maintain full protection. Live attenuated vaccines are in use against flu, measles, mumps, and tuberculosis. In the latter case, an attenuated strain of the mycobacterium that causes the disease is used (Bacille Calmette-Guerin; BCG). Although live attenuated poliovirus was used as a vaccine until recently, its use was discontinued because the risk of reemergence, by mutation, of more virulent strains of the poliovirus outweighed the benefit. Currently, killed poliovirus is used as the vaccine of choice in the United States and Europe, although live attenuated poliovirus vaccines continue to be used elsewhere.

Vaccines based on the cowpox virus, a close relative of the human variola virus that causes smallpox, have been used successfully to eradicate smallpox, the first such example of the elimination of an infectious disease. Attempts to achieve a similar feat for polio are nearing completion, but socioeconomic and political factors or armed conflict often complicate the administration of vaccines, leading to reemergence of the disease, as seen recently in Asia.

The other major type of vaccine is called a subunit vaccine. Rather than live attenuated strains of a virulent bacterium or virus, only one or several of its components (a subunit of the entire pathogen) are used to elicit immunity. In certain cases, this approach is sufficient to afford lasting protection against a challenge with the live, virulent source of the antigen used for vaccination. It has been successful in preventing infections with the hepatitis B virus. The commonly used flu vaccines are composed mainly of the envelope proteins neuraminidase and hemagglutinin (see Figure 3-11); these vaccines elicit neutralizing antibodies. For the vaccine against human papillomavirus HPV 16, a serotype that causes cervical cancer, viruslike particles composed of the virus’s capsid structural proteins but devoid of its genetic material are generated; these particles are noninfectious, yet in many respects mimic the intact virion. The HPV vaccine now licensed for use in humans is expected to reduce the incidence of cervical cancer in susceptible populations by perhaps as much as 80 percent, the first example of a vaccine that prevents a particular type of cancer.

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From a public health perspective, cheaply produced and widely distributed vaccines are formidable tools for preventing or even eradicating communicable diseases. Current efforts are aimed at producing vaccines against diseases for which no other suitable therapies are available (Ebola virus) or where socioeconomic conditions have made the distribution of drugs problematic (malaria, HIV). With a more complete understanding of how the immune system operates, it should be possible to improve on the design of existing vaccines and extend these principles to diseases for which no successful vaccines are currently available. A remaining challenge is the massive genetic variation that pathogens can acquire: the error-prone reverse transcriptase of HIV introduces mutations with every successive cycle of viral replication, creating untold numbers of variants. Viable variants that carry such mutations may escape detection by the immune system. The design of effective vaccines must therefore be focused on those structural elements that do not tolerate mutations and that can be “seen” by the adaptive immune system.