T cell-independent antigen (e.g., the type b capsular polysaccharide of Haemophilus influenzae or pneumococcal capsular polysaccharides) into a T cell-dependent antigen. Such conjugate vaccines are immunogenic in infants, inducing high-affinity IgG antibody and long-term immunological memory, whereas none of these features occurs when the polysaccharide alone is used as a vaccine. The basis for this is that the polysaccharide-protein conjugate will bind to and partially activate B cells that are specific for the polysaccharide, which internalize the conjugate, then process and present peptides from the protein component to CD4+ (helper) T cells specific for these peptides. This leads to activation of the T cells, that in turn help the B cells to produce high-affinity antibodies to the linked polysaccharide and mature into long-term memory B cells. In competition with these polysaccharide-specific B cells, are other B cells specific for the protein component of the conjugate. These B cells also present peptides to CD4+ T cells and in turn receive second signals allowing them to produce antibodies to the protein component of the conjugate vaccine. If the numbers of CD4+ T cells specific for the protein are limiting, then B cells specific for the polysaccharide component and B cells specific for the protein component of the conjugate are in competition with each other for limited numbers of CD4+ T cells capable of providing help (Insel, 1995). A variant of this can occur if multiple different carbohydrate antigens are conjugated to the same protein. In this case, the B cells specific for different carbohydrates may compete with each other for limited numbers of CD4- T cells. The latter situation may account in part for reduced responses seen when multivalent pneumococcal-tetanus toxoid conjugate vaccine was given along with H. influenzae type b-tetanus toxoid conjugate vaccine (Dagan et al., 1998).

Competition for Antigen Presentation

This describes a situation in which T cells responding to one antigen or infection compete with other T cells that are responding during the same time frame to other antigens or another infection, and one of the responses has a head start—it precedes the other by a few days or weeks. This gives the response to the earlier challenge a competitive advantage, such that it dominates and impedes the response to the delayed antigenic challenge or infection. Such competition is most readily observed in the context of strong CD8 T cell responses to viral infections (Chen, HD, 2001; Selin et al., 1998, 1999) or artificially manipulated immune responses (Kedl, 2000) in experimental animals. Bystander effects, including viral immune interference (see IOM, 2001a for more details) rather than competition for antigen presentation may affect responses to heterologous viral infections. An example of a heterologous effect in humans is the recent findings related to the timing of administration of MMR vaccine and varicella vaccine. If MMR and varicella vaccine are given at the same time or an interval of 30 or more days elapses between the administration of MMR and varicella vaccines, MMR and



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