Abstract
Vaccines play a vital role in protecting our communities against infectious disease. Unfortunately, some vaccines provide only partial protection or in some cases vaccine-mediated immunity may wane rapidly, resulting in either increased susceptibility to that disease or a requirement for more booster vaccinations in order to maintain immunity above a protective level. The durability of antibody responses after infection or vaccination appears to be intrinsically determined by the structural biology of the antigen, with multivalent protein antigens often providing more long-lived immunity than monovalent antigens. This forms the basis for the Imprinted Lifespan model describing the differential survival of long-lived plasma cell populations. There are, however, exceptions to this rule with examples of highly attenuated live virus vaccines that are rapidly cleared and elicit only short-lived immunity despite the expression of multivalent surface epitopes. These exceptions have led to the concept that multivalency alone may not reliably determine the duration of protective humoral immune responses unless a minimum number of long-lived plasma cells are generated by reaching an appropriate antigenic threshold of B cell stimulation. Examples of long-term and in some cases, potentially lifelong antibody responses following immunization against human papilloma virus (HPV), Japanese encephalitis virus (JEV), Hepatitis B virus (HBV), and Hepatitis A virus (HAV) provide several lessons in understanding durable serological memory in human subjects. Moreover, studies involving influenza vaccination provide the unique opportunity to compare the durability of hemagglutinin (HA)-specific antibody titers mounted in response to antigenically repetitive whole virus (i.e., multivalent HA), or detergent-disrupted “split” virus, in comparison to the long-term immune responses induced by natural influenza infection. Here, we discuss the underlying mechanisms that may be associated with the induction of protective immunity by long-lived plasma cells and their importance in future vaccine design.
Highlights
During an antigenic insult triggered by vaccination or infection, a series of immunological events unfold including the activation, proliferation, differentiation, and coordination of antigenspecific B cells and T cells that, if successful, will develop into an appropriate immune response that provides protective immunity upon re-encounter with the pathogen of interest
This finding was in stark contrast to the long-lived serum antibody responses that are commonly found after infection or vaccination and this led to several memory B cells (MBC)-dependent theories for maintaining long-term antibody production, mostly involving reactivation and proliferation of MBC in order to repopulate short-lived plasma cell numbers
B cell depletion experiments performed in non-human primates (NHP) provides another useful approach by combining the attributes of a versatile animal model with the ability to measure long-term antibody responses that can be followed for many years similar to those achieved in clinical studies
Summary
During an antigenic insult triggered by vaccination or infection, a series of immunological events unfold including the activation, proliferation, differentiation, and coordination of antigenspecific B cells and T cells that, if successful, will develop into an appropriate immune response that provides protective immunity upon re-encounter with the pathogen of interest. This indicates that in practice, the yeast-derived HBsAg/VLPs produced in clinical vaccine preparations may often be dimeric or constitute even larger agglomerates (confirmed by electron microscopy) and if these antigenic preparations are aggregates [60, 73] that have a disregular order, we speculate that multimeric crosslinking of the B cell receptor (BcR) on antigen-specific B cells could be suboptimal This may explain why antiviral antibodies mounted against the HBsAg subviral particles have a half-life that is more similar to alum-adjuvanted nonrepetitive proteins such as tetanus and diphtheria, rather than the more long-lived antibody responses induced by the highly repetitive structures on HAV particles within the same vaccine formulation (Figure 2C).
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