Rescuing Immunosenescence via Non-Specific Vaccination

Alexander I Mosa

doi:10.3390/immuno1030015

Abstract

Discrepancies in lifespan and healthy-life span are predisposing populations to an increasing burden of age-related disease. Accumulating evidence implicates aging of the immune system, termed immunosenescence, in the pathogenesis of multiple age-related diseases. Moreover, immune dysregulation in the elderly increases vulnerability to infection and dampens pathogen-specific immune responses following vaccination. The health challenges manifesting from these age related deficits have been dramatically exemplified by the current SARS-CoV-2 pandemic. Approaches to either attenuate or reverse functional markers of immunosenescence are therefore urgently needed. Recent evidence suggests systemic immunomodulation via non-specific vaccination with live-attenuated vaccines may be a promising avenue to at least reduce aged population vulnerability to viral infection. This short review describes current understanding of immunosenescence, the historical and mechanistic basis of vaccine-mediated immunomodulation, and the outstanding questions and challenges required for broad adoption.

Highlights

Life expectancy is outpacing healthy-life expectancy in developed nations [1]
Attenuating age-related immune dysregulation is an urgent public health priority, with recent initiatives focusing on the potential of adjuvantation and non-specific vaccination to resuscitate immune function [3,4]
Deficits in adaptive immune responses following vaccination only partially describe the challenge of immunosenescence, with accompanying dysfunction in innate immunity aggregating in systemic, refractory inflammation termed “inflammageing”, which may increase susceptibility to multiple age-related diseases with convergent inflammatory pathogenesis, such as diabetes, atherosclerosis, and cancer [5]

Summary

Introduction

Life expectancy is outpacing healthy-life expectancy in developed nations [1]. Increased lifespan without a concomitant increase in health span is partly attributable to immunosenescence, a phenomena characterized by a progressive reduction in circulating PBMCs and basal elevations in pro inflammatory cytokines, manifesting as increased vulnerability to infection, reduced immunosurveillance, impaired proteostasis, and activation of latent viruses [1,2]. Recent analysis using a composite outcome of COVID-19 related mortality suggests a 10.4% reduction for every 10% increase in the population-wide BCG index, an estimation of country-specific BCG vaccination coverage [14] Supporting this finding, a separate analysis observed reduced COVID-19 disease burden among countries with universal BCG vaccination [15]. More recent analysis indicates that these reductions may not be attributable to NSE, but rather to the immunosuppressive effects of measles infection, which may increase vulnerability to subsequent infections [28] These findings suggest MV is not reducing mortality by NSE, including heterologous immunity, but is reducing undercounted measles-related morbidity—which would be consistent with a measles-specific protective mechanism [29]. Interpreting reductions in child mortality following MV, even in randomized settings, such as the more recent 2010 trial in Guinea-Bissau, which observed reduced incidence of infection requiring hospitalization, is complicated by measles specific virology [30]. Along with a separate Finnish study comparing OPV to IPV, which found a protective effect against ear infections, these findings suggest the protective effect of OPV is greater than its polio-specific reductions in morbidity [34]

Proposed Mechanisms of Immunomodulation

Findings

Conclusions and Perspectives