Chapter 116. Immunization Principles and Vaccine Use (Part 3) The Immune Response While many constituents of infectious microorganisms and their products (e.g., exotoxins) are or can be rendered immunogenic, only some stimulate protective immune responses that can prevent infection and/or clinical illness or (as in the case of rotavirus) can attenuate illness, providing protection against severe disease but not against infection or mild illness. The immune system is complex, and many factors—including antigen composition and presentation as well as host characteristics—are critical for stimulation of the desired immune responses (Chap. 308). The Primary Response The primary response to a vaccine antigen includes an apparent latent period of several days before immune responses can be detected. Although the immune system is rapidly activated, it takes 7–10 days for activated B lymphocytes to produce enough antibody to be detected in the circulation. The primarily IgM antibodies seen initially are rapidly produced but have only a low affinity for the antigen. After the first week, high-affinity IgG antibodies begin to be produced in quantity; this switch from IgM to IgG production requires the participation of CD4+ T-helper lymphocytes—the "middle men" of the immune response. Because precursors for T cells mature within the thymus gland, antigens that stimulate T cells are referred to as T or thymus-dependent antigens. Circulating antigen-specific T lymphocytes that implement cell-mediated immune responses are identified in the peripheral bloodstream only after several days but begin to increase in number immediately after antigenic stimulation. Activation of these responses typically requires co-recognition of the antigen by specific molecular species of HLA, the major histocompatibility complex, which is present on the surface of lymphocytes and macrophages. Some individuals cannot respond to one or more antigens, even when repeatedly exposed, because they do not have the genes for the particular HLA type involved in antigen recognition, processing, and presentation for an immune response. This situation is known as primary vaccine failure. The Secondary Response Stronger and faster humoral or cell-mediated responses are elicited by a second exposure to the same antigen and are detectable within days of the "booster" dose. The secondary response depends on immunologic memory induced by the primary exposure and is characterized by a marked proliferation of IgG antibody–producing B lymphocytes and/or effector T cells. Pure polysaccharide antigens, such as the first-generation pneumococcal vaccine, evoke immune responses that are independent of T cells and are not enhanced by repeated administration. However, conjugation of the same polysaccharide to a suitable protein converts the carbohydrate antigen into one that is T cell– dependent and able to induce immunologic memory and secondary responses to reexposure. Although levels of vaccine-induced antibodies may decline over time, revaccination or infection generally elicits a rapid (anamnestic) protective secondary response consisting of IgG antibodies, with little or no detectable IgM. Thus, a lack of measurable antibody in an immunized individual does not necessarily indicate secondary vaccine failure. Similarly, the mere presence of detectable antibodies after immunization does not ensure clinical protection: the level of circulating antibody may need to exceed a threshold value in order to mediate protection (e.g., 0.01 IU/mL for tetanus antitoxin). Mucosal Immunity Some pathogens are confined to and replicate only at mucosal surfaces (e.g., Vibrio cholerae), whereas others first encounter the host at a mucosal surface before they invade systemically (e.g., influenza virus). A distinctive immunoglobulin, secretory IgA, is produced at mucosal surfaces and is adapted to resist degradation and to function at these sites. Vaccines may be specifically designed to induce secretory IgA and thereby to block the essential initial steps in disease pathogenesis that occur on mucosal surfaces. Given its complexity, mucosal immunology has become a separate branch of the field of immunology. Measurement of the Immune Response Immune responses to vaccines are often gauged by the concentration of specific antibody in serum. Although seroconversion (i.e., transition from antibody-negative to antibody-positive status) serves as a dependable indicator of an immune response, it does not necessarily correlate with protection unless serum antibody is the critical mechanism in vivo and the levels achieved are sufficient (e.g., against measles). In some instances, serum antibody correlates with clinical protection but does not directly mediate it (e.g., vibriocidal serum antibodies in cholera). Herd Immunity Successful vaccination protects immunized individuals from infection, thereby decreasing the percentage of susceptible persons within a population and reducing the possibility of infection transmission to others. At a definable prevalence of immunity, an infectious organism can no longer circulate freely among the remaining susceptibles. This indirect protection of unvaccinated (nonimmune) persons is called the herd immunity effect; through this effect, vaccination programs may confer societal benefits that exceed individual costs. The level of vaccine coverage needed to elicit herd immunity depends on the patterns of interaction among individuals within the population and the biology of the specific infectious agent. For example, measles virus and VZV have high transmission rates and require a higher level of vaccine coverage for herd immunity than do organisms with lower transmission rates, such as S. pneumoniae. Wherever herd immunity for poliomyelitis and measles has been induced with vaccines, transmission of infection has ceased; however, herd immunity may wane if immunization programs are interrupted (as was the case for diphtheria in the former Soviet Union) or if a sufficient percentage of individuals refuse to be immunized because of a fear of vaccine-related adverse events (as occurred for pertussis in the United Kingdom and Japan). In either setting, the loss of herd immunity has led to renewed circulation of the organism and subsequent large outbreaks with serious consequences. . Chapter 116. Immunization Principles and Vaccine Use (Part 3) The Immune Response While many constituents of infectious microorganisms and their products (e.g.,. produced at mucosal surfaces and is adapted to resist degradation and to function at these sites. Vaccines may be specifically designed to induce secretory IgA and thereby to block the essential. sufficient percentage of individuals refuse to be immunized because of a fear of vaccine- related adverse events (as occurred for pertussis in the United Kingdom and Japan). In either setting, the