2 Vaccine Immunology Claire-Anne Siegrist To generate vaccine-mediated protection is a complex chal- non–antigen-specifc responses possibly leading to allergy, lenge. Currently available vaccines have largely been devel- autoimmunity, or even premature death—are being raised. oped empirically, with little or no understanding of how they Certain “off-targets effects” of vaccines have also been recog- activate the immune system. Their early protective effcacy is nized and call for studies to quantify their impact and identify primarily conferred by the induction of antigen-specifc anti- the mechanisms at play. The objective of this chapter is to bodies (Box 2.1). However, there is more to antibody- extract from the complex and rapidly evolving feld of immu- mediated protection than the peak of vaccine-induced nology the main concepts that are useful to better address antibody titers. The quality of such antibodies (e.g., their these important questions. avidity, specifcity, or neutralizing capacity) has been identi- fed as a determining factor in effcacy. Long-term protection HOW DO VACCINES MEDIATE PROTECTION? requires the persistence of vaccine antibodies above protective thresholds and/or the maintenance of immune memory cells Vaccines protect by inducing effector mechanisms (cells or capable of rapid and effective reactivation with subsequent molecules) capable of rapidly controlling replicating patho- microbial exposure. The determinants of immune memory gens or inactivating their toxic components. Vaccine-induced induction, as well as the relative contribution of persisting immune effectors (Table 2.1) are essentially antibodies— antibodies and of immune memory to protection against spe- produced by B lymphocytes—capable of binding specifcally cifc diseases, are essential parameters of long-term vaccine to a toxin or a pathogen.2 Other potential effectors are cyto- effcacy. toxic CD8+ T lymphocytes that may limit the spread of infec- The predominant role of B cells in the effcacy of current tious agents by recognizing and killing infected cells or vaccines should not overshadow the importance of T-cell secreting specifc antiviral cytokines and CD4+ T-helper (Th) responses: T cells are essential to the induction of high-affnity lymphocytes. These Th cells may contribute to protection antibodies and immune memory, directly contribute to the through cytokine production and provide support to the gen- protection conferred by current vaccines such as bacille eration and maintenance of B and CD8+ T-cell responses. Calmette-Guérin (BCG), may play a more critical role than Effector CD4+ Th cells were initially subdivided into T-helper previously anticipated for specifc diseases like pertussis, and 1 (Th1) or T-helper 2 (Th2) subsets depending on their main will be the prime effectors against novel vaccine targets with cytokine production (interferon-γ or interleukin [IL]-4), predominant intracellular localization such as tuberculosis. respectively. This dichotomy became outdated as Th cells were New methods have emerged allowing the assessment of a increasingly shown to include a large number of subsets with growing number of vaccine-associated immune parameters, distinct cytokine-producing and homing capacities (see Table including in humans. This development raises new questions 2.1).3 A recently identifed critical subset of vaccine-induced about the optimal markers to assess and their correlation with CD4+ Th cells are follicular T-helper (Tfh) cells: they are spe- vaccine-induced protection. The identifcation of mechanistic cially equipped and positioned in the lymph nodes to support immune correlates—or at least surrogates—of vaccine effcacy potent B-cell activation and differentiation into antibody- is a major asset for the development of new vaccines or the secreting-cells4 and were identifed as directly controlling anti- optimization of immunization strategies using available vac- body responses and mediating adjuvanticity.5–7 Another cines. Thus, their determination generates a considerable important subset are T-helper 17 (Th17) cells which essen- amount of interest. During the last decade, the increased tially defend against extracellular bacteria that colonize the awareness of the complexity of the immune system and its skin and mucosa, recruiting neutrophils and promoting local determinants, including at the host genetic level, indicated infammation.8,9 These effectors are controlled by regulatory T that using system biology approaches to assess how various cells (Tregs) involved in maintaining immune tolerance.10 processes and networks interact in response to immunization Most antigens and vaccines trigger B- and T-cell responses, could prove more illustrative than trying to isolate and char- such that there is no rationale in opposing vaccines favoring acterize a few components of vaccine responses.1 Delineating antibody production (“humoral immunity”) and T-cell the specifc molecular signatures of vaccine immunogenicity responses (“cellular immunity”). In addition, CD4+ T cells are is beginning to highlight novel correlates of protective immu- required for most antibody responses, whereas antibodies nity and better explain the heterogeneity of vaccine responses exert signifcant infuences on T-cell responses to intracellular in a population. The tailoring of vaccine strategies for specifc pathogens.11 vulnerable populations, including very young, elderly, and immunosuppressed populations, also largely relies on a better What Are the Main Effectors of understanding of what supports or limits vaccine effcacy Vaccine Responses? under special circumstances—at the population and individ- ual levels. Lastly, the exponential development of new vaccines The nature of the vaccine exerts a direct infuence on the type raises many questions that are not limited to the targeted of immune effectors that are elicited and that mediate protec- diseases and the potential impacts of their prevention, but that tive effcacy (Table 2.2). address the specifc and nonspecifc impacts of such vaccines Capsular polysaccharides (PSs) elicit B-cell responses in on the immune system and, thus, on health in general. These what is classically reported as a T-independent manner.12 The immune-related concerns have largely spread into the conjugation of bacterial PS to a protein carrier (e.g., glyco- population, and questions related to the immunological conjugate vaccines) provides foreign peptide antigens that safety of vaccines—that is, their capacity for triggering are presented to the immune system and, thus, recruit 16 Vaccine Immunology 17 BOX 2.1 Main Immunological Definitions 2 ADJUVANT CD8+ T CELLS Agents that increase the stimulation of the immune system by Lymphocytes that specialize in the killing of infected cells, through enhancing antigen presentation (depot formulation, delivery direct contact or cytokine (IFN-γ, TNF-α) production. systems) and/or by providing costimulation signals CENTRAL MEMORY T CELLS (immunomodulators). Aluminum salts are most often used in Memory T cells traffick through the lymph nodes, ready to today’s vaccines. proliferate and generate a high number of effector cells in AFFINITY, AVIDITY response to specific microbial peptides. Antibody affinity refers to the tendency of an antibody to bind to a CHEMOKINES specific epitope at the surface of an antigen; that is, to the Small secreted proteins that function as chemoattractants, strength of the interaction. Avidity is the sum of the epitope- recruiting cells that express the corresponding chemokine specific affinities for a given antigen. It directly relates to its receptors at their surface and thus migrating toward higher function. concentrations of chemokines. AFFINITY MATURATION COSTIMULATORY MOLECULES Processes through which antigen-specific B cells undergo somatic Molecules that become expressed at the surface antigen- hypermutation and affinity-based selection, resulting in B cells that presenting cells on activation and deliver stimulatory signals to produce antibodies with increased affinity over germline other cells, namely T and B cells. antibodies. DENDRITIC CELLS ANTIBODIES Cells that constantly sample their surroundings for pathogens Proteins of the immunoglobulin family, present on the surface of B such as viruses and bacteria, detect dangers, and initiate immune lymphocytes, secreted in response to stimulation, that neutralize responses. Immature patrolling dendritic cells (DCs) have high antigens by binding specifically to their surface. endocytic activity and a low T-cell activation potential. Contact ANTIGEN-PRESENTING CELLS with a pathogen induces maturation and the expression of certain Cells that capture antigens by endocytosis or phagocytosis, cell-surface molecules, greatly enhancing their ability to activate T process them into small peptides, display them at their surface cells. through major histocompatibility complex (MHC) molecules, and EFFECTOR MEMORY T CELLS provide costimulation signals that act synergistically to activate Memory T cells patrol through the body to detect specific antigen-specific T cells. Antigen-presenting cells include B cells, microbial peptides and are capable of an immediate cytotoxic macrophages, and dendritic cells, although only dendritic cells are function in case of recognition. capable of activating naïve T cells. EXTRAFOLLICULAR REACTION B LYMPHOCYTES B-cell differentiation pathways that occur outside of germinal Cells that originate in the bone marrow, mature in secondary centers in response to protein or