Another obstacle is that even when a vaccine such as that against measles can be used effectively in developed countries, technical and economic problems can prevent its widespread use in developing countries, where mortality from these diseases is still high. For example, simple costs of storage and deployment can be significant barriers to the use of existing vaccines in poorer countries. Therefore, the development of vaccines therefore remains an important goal of immunology, and the latter half of the 20th century saw a shift to a more rational approach based on a detailed molecular understanding of microbial pathogenicity, analysis of the protective host response to pathogenic organisms, and an understanding of the regulation of the immune system to generate effective Tand B-lymphocyte responses.
16-21 Most effective vaccines generate antibodies that prevent the damage caused by toxins or that neutralize the pathogen and stop infection.
Although the requirements for generating protective immunity vary with the nature of the infecting organism, many effective vaccines currently work by inducing antibodies against the pathogen. For many pathogens, including extracellular organisms and viruses, antibodies can provide protective immunity. This is not the case for all pathogens, unfortunately; some may require additional cell-mediated immune responses such as those mediated by CD8 T cells.
Effective protective immunity against some microorganisms requires the presence of preexisting antibody at the time of infection, either to prevent the damage caused by the pathogen or to prevent reinfection by the pathogen altogether. The first case is illustrated by vaccines against tetanus and diphtheria, whose clinical manifestations of infection are due to the effects of extremely powerful exotoxins (see Fig. 10.31). Preexisting antibody against the exotoxin is necessary to provide a defense against these diseases. Indeed, the tetanus exotoxin is so powerful that the tiny amount that can cause disease may be insufficient to lead to a protective immune response; consequently, even survivors of tetanus require vaccination to be protected against the risk of subsequent attack.
The second way in which antibodies can protect is by preventing infection a second time by the same pathogen, as in the case of certain viral infections. While CD8 T cells are able to kill already virally infected cells during an infection, antibodies are able to prevent infection of cells by the virus in the first place. This action is called neutralization. The ability of an antibody to neutralize a pathogen may depend on its affinity, its isotype subclass, complement, and the activity of phagocytic cells. For example, preexisting antibodies are required to protect against the polio virus, which infects critical host cells within a short period after entering the body and is not easily controlled by T lymphocytes once intracellular infection has been established. Vaccines against seasonal influenza virus provide protection in this same manner, by inducing antibodies that reduce the chance of a second infection by the same strain of influenza. For many viruses, antibodies produced by an infection or by vaccination can neutralize the virus and prevent further spread of infection, but this is not always the case. In HIV infection, despite the generation of antibodies that can bind to surface viral epitopes, most of these antibodies fail to neutralize the virus. In addition, HIV has many different strains, or clades, and most vaccines based on HIV proteins do not induce antibodies that neutralize all clades, presenting a challenge for effective vaccine design. However, a recent clinical trial suggests that boosting previously vaccinated subjects with protein 5–7 years after immunization may induce some antibodies with crossclade activity.