Figure 4.

Imprinted lifespan model of humoral immunity. Prior longitudinal studies have indicated that different vaccine and virus antigens elicit serum antibody responses of varying duration (58). Since long-lived PC are terminally-differentiated non-dividing cells that can survive for months or even years after the initial antigenic insult has been resolved (27), our hypothesis is that PC lifespan must be determined or “imprinted” at the time of B cell activation during the initial stages of an active immune response. Microbes such as viruses and bacteria have surface antigens that are highly repetitive and these structural attributes are likely to cause increased B cell activation by binding to multiple immunoglobulin molecules on the responsive B cell and trigger increased signal transduction in comparison to B cell activation induced by non-repetitive or monovalent antigens. B cell activation is further enhanced via T cell help during T-dependent immune responses to foreign antigens. In addition to the structural attributes of a particular antigen, another important parameter is antigenic load (118). If an infection is resolved too quickly or if a vaccine has low antigen content, is rapidly degraded, or contains no adjuvant, then there will be fewer germinal center reactions, fewer activated B cells and T cells, and fewer PC that enter the long-lived pool. Bearing this in mind, we postulate that a certain antigenic threshold must be met in order to elicit a sufficient number of PC to maintain antibody responses above a protective threshold (shown as a dashed line in each graph) and this set point will differ depending on the level of protection needed for each pathogen or toxin. Contemporary detergent-disrupted influenza vaccines provide an example of non-adjuvanted non-repetitive antigen that does not reach the antigenic threshold. Under these circumstances, transient, low levels of immunity rapidly wane to below a protective threshold, often before the end of single influenza season. In contrast, booster vaccination against other non-repetitive alum-formulated antigens such as tetanus or diphtheria is able to elicit high antibody titers that decline faster than that observed with highly repetitive viral antigens (58), but nevertheless provide long-term immunity that may last for decades. Among repetitive antigens, the duration of immunity is also likely to be influenced by antigenic threshold. For highly attenuated vaccine strains of viruses such as MVA or Dengvaxia (Table 1), viral antigen may be cleared too quickly, resulting in the induction of fewer long-lived PC due to insufficient antigen load with an end-result of long-term antibody production that resides near or below the protective threshold. On the other hand, natural infections with viruses such as measles, vaccinia, influenza, etc., (Table 1) or immunization with optimized and adjuvanted VLP or whole-virus vaccines (Figures 1, 2) will potentially induce lifelong immunity by presenting repetitive epitopes while also achieving sufficient antigenic load that, together with appropriate T cell help, will result in long-term antibody production that is maintained at or above protective levels.