Immunological mechanisms of vaccination

Abstract

Vaccines represent one of the greatest triumphs of modern medicine. Despite the common origins of vaccinology and immunology more than 200 years ago, the two disciplines have evolved along such different trajectories that most of the highly successful vaccines have been made empirically, with little or no immunological insight. Recent advances in innate immunity have offered new insights about the mechanisms of vaccine-induced immunity and have facilitated a more rational approach to vaccine design. Here we will discuss these advances and emerging themes on the immunology of vaccination.

Figures

Figure 1

Varieties of antibody responses and their correlates of protection. Antibody responses to vaccination or infection can be qualitatively distinct and can be measured in different ways. Thus, all the antigen-specific binding antibodies to a given antigen can be measured by enzyme-linked immunosorbent assay (ELISA), and the affinity or avidity of antibodies can be assessed by surface plasmon resonance, with those antibodies having an affinity above a certain threshold being deemed high-affinity antibodies. The ability to neutralize the pathogen in vitro is one measure of antibody function. Other correlates include the ability to kill a pathogen by opsonophagocytosis, complement fixation, antibody-dependent cytotoxic cell killing, isotype and persistence. The correlates of protection provided by different vaccines differ in the aforementioned parameters; for example, correlates for polio, measles, rabies, diphtheria or tetanus are considered to be binding antibody titers assessed by enzyme-linked immunosorbent assay, and so on. Hib, H. influenzae type B; VZV, varicella zoster virus.

Figure 2

Programming antibody responses with innate immunity. Antigen-specific antibody responses to T cell–dependent antigens develop along two anatomically and functionally distinct pathways–. DC-mediated stimulation of antigen-specific TH cells in the T cell–rich areas is regulated by the DC subset and the PRRs triggered. Activated antigen-specific B cells migrate to the interface between the B cell follicle and T cell area–. Here, they interact with helper T cells, which results in the clonal expansion of B cells; these migrate to the bridging channels at the edges of the lymphoid areas of the spleen or the medullary cords in the lymph nodes and differentiate into short-lived plasma cells–. Other activated B cells migrate into B cell follicles and proliferate rapidly and form germinal centers (GC). In addition, some helper T cells (TFH cells) express CXCR5 and migrate into the follicles. Induction of TFH cells is controlled by the nature of the DC subset, innate cytokines, TLR ligands, costimulatory molecules, TLR ligands and so on. In the early phase of GC development, the dividing B cells (centroblasts) downregulate cell surface expression of immunoglobulin and undergo somatic hypermutation of their immunoglobulin genes–. Then, the centroblasts cease to divide and re-express their mutated immunoglobulin receptor, and cells (centrocytes) with heightened affinity for the antigen are thought to be selected for enhanced affinity of binding to antigen-antibody complexes on the follicular DCs, as well as by helper T cells in the light zone. Positively selected centrocytes differentiate into long-lived plasma cells that migrate to the bone marrow or differentiate into recirculating memory B cells. The survival of long lived plasma cells or memory B cells is controlled by innate parameters such as TLR ligands, basophils, BAFF or APRIL.