Harnessing the beneficial heterologous effects of vaccination

Abstract

Clinical evidence strongly suggests that certain live vaccines, in particular bacille Calmette-Guérin (BCG) and measles vaccines, can reduce all-cause mortality, most probably through protection against non-targeted pathogens in addition to the targeted pathogen. The underlying mechanisms are currently unknown. We discuss how heterologous lymphocyte activation and innate immune memory could promote protection beyond the intended target pathogen and consider how vaccinologists could leverage heterologous immunity to improve outcomes in vulnerable populations, in particular the very young and the elderly.

Figure 1. Heterologous lymphocyte responses

a | Some heterologous effects may be attributed to antigen-specific mechanisms that generate lymphocytes whose antigen receptors are cross-reactive for distinct microbial or host antigens due to molecular mimicry. Alternatively, a vaccine may induce bystander activation of memory lymphocytes to sustain levels of antibodies directed against other targets. b | Heterologous lymphocyte responses can induce protection against unrelated pathogens via antigen-specific bystander lymphocytes or induction of antigen non-specific innate mechanisms such as cytokine production to activate macrophages.

Figure 2. Mechanisms of innate memory in monocytes and macrophages

Initial exposure of monocytes/macrophages or their progenitors to certain microbial stimuli induces epigenetic marks and metabolic changes that persist for extended periods and influence the subsequent responses of these cells to the same or distinct stimuli. a | Priming/training increases the subsequent response, whereas tolerance reduces responsiveness. b | Priming/training and tolerance can occur simultaneously within the same cell, with expression of some genes being promoted and others suppressed. c | Innate memory effects may be long-lived due to the persistence of self-renewing macrophages in tissues, or exposed progenitors that continue to yield monocytes and macrophages with altered function for extended periods. Innate memory may be maintained indefinitely or wane over time.