Factors That Govern the Induction of Long-Lived Antibody Responses.

Bryce Chackerian,David S Peabody

doi:10.3390/v12010074

Abstract

The induction of long-lasting, high-titer antibody responses is critical to the efficacy of many vaccines. The ability to produce durable antibody responses is governed by the generation of the terminally differentiated antibody-secreting B cells known as long-lived plasma cells (LLPCs). Once induced, LLPCs likely persist for decades, providing long-term protection against infection. The factors that control the generation of this important class of B cells are beginning to emerge. In particular, antigens with highly dense, multivalent structures are especially effective. Here we describe some pathogens for which the induction of long-lived antibodies is particularly important, and discuss the basis for the extraordinary ability of multivalent antigens to drive differentiation of naïve B cells to LLPCs.

Highlights

B-Cell Responses to VaccinationMost of the effective vaccines in use today work by inducing humoral immune responses.Activation of naïve B cells by vaccine antigens leads to a series of events which result in the production of memory B cells and differentiation into two classes of antibody secreting cells, short-lived plasmablasts and long-lived plasma cells (LLPCs)
Subsequent studies demonstrated that vaccines consisting of self-antigens arrayed on the surface of the virus-like particles (VLPs) could effectively induce anti-self antibody responses [52,53], that this ability is critically dependent on the density of the self-antigens displayed on VLPs [54,55], and that these interactions may be mediated by binding to surface-expressed IgD on naïve B cells [56]. These findings have led to the development of vaccine candidates that induce antibodies against self-antigens involved in chronic diseases, including angiotensin II [57], PCSK9 [58], tau
We showed that upregulation of these molecules upon stimulation by VLPs is in anergic transgenic B cells, relative to non-anergic cells [24]

Summary

Introduction—B-Cell Responses to Vaccination

Most of the effective vaccines in use today work by inducing humoral immune responses. There are a number of important pathogens for which vaccine-based induction of memory cells alone is insufficient to provide protective immunity In these cases, protection depends on a pre-existing level of antibodies high enough to entirely prevent the initial infection event, because once one of these agents initiates an infection, it establishes a beachhead which is partially or completely resistant to antibody effector activity. In GCs, B cells compete for binding with antigens displayed on follicular dendritic cells, and present antigens to follicular T helper cells, which in turn provide survival signals to the B cell This process does not require a multivalent antigen, enhanced B-cell crosslinking in GCs leads to increased GC B-cell proliferation and promotes differentiation to plasma cells, in scenarios in which T help is limiting [25]. It is likely that multivalency can exert its stimulatory effects at multiple steps during the B-cell activation and differentiation process

Immune Responses Elicited by Multivalent Vaccines

Mice immunized with dose a single ofwithout an EGFRvIII peptide to or

The Special Case of Using Multivalent Vaccines to Break B-Cell Tolerance

Conclusions