Abstract
Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4+ T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against “drifted” (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 “swine” flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8+ T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such “memory” cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8+ CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 “Spanish flu,” which killed more than 50 million people worldwide.
Highlights
Successful vaccination relies on the induction of long-term immunological memory
We focus on the nature of optimal memory B cell and T cell generation and ask how we might use this knowledge to overcome the limitations of seasonal influenza vaccines by developing feasible strategies for both inducing and maintaining long-term, cross-reactive immunological memory
The global World Health Organisation (WHO) network closely monitors the circulation of influenza viruses in humans and other species, including birds, across the northern and southern hemispheres, whereby information derived from the antigenic and genetic characterization of these strains, along with epidemiological data, is used to select the strains to be incorporated into an upcoming seasonal vaccine [26]
Summary
Successful vaccination relies on the induction of long-term immunological memory. Exposure to an infectious virus elicits acute effector responses that mediate acute pathogen control, along with the generation and maintenance of T cell and B cell memory capable of protecting against re-exposure. The global WHO network closely monitors the circulation of influenza viruses in humans and other species, including birds, across the northern and southern hemispheres, whereby information derived from the antigenic and genetic characterization of these strains, along with epidemiological data, is used to select the strains to be incorporated into an upcoming seasonal vaccine [26]. Firstinfection ferret antisera is used to identify and characterize new influenza strains, yet repeated exposures to A/H3N2 variants affect Ab quantity and quality, which makes vaccine-strain selection even more challenging [35] Both immunological responses to influenza viruses and influenza vaccine effectiveness are undoubtedly affected by the combination of antigenic drift and prior immunity. Influenza virus evolution has been widely studied, yet it is still largely unknown how cross-reactive B cell memory impacts on Ab responses to new strains
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