Aging and influenza vaccine-induced immunity

Highlights

• Vaccine effectiveness is reduced in the elderly population because of immunosenescence.

• New vaccine strategies should focus on countering immunosenescence.

• Strategies focusing on changes in repertoire diversity should be prioritized.

• Strategies improving T and B cell subset distribution should be devised.

Abstract

Immunosenescence is defined as the progressive deterioration of the immune system with aging. Immunosenescence stifles the generation of protective B and T cell-mediated adaptive immunity in response to various pathogens, resulting in increased disease susceptibility and severity in the elderly population. In particular, immunosenescence has major impacts on the phenotype, function, and receptor repertoire of B and T cells in the elderly, hindering protective responses induced by seasonal influenza virus vaccination. In order to overcome the detrimental impacts of immunosenescence on protective immunity to influenza viruses, we review our current understanding of the effects of aging on adaptive immune responses to influenza and discuss current and future avenues of vaccine research for eliciting more potent anti-influenza immunity in the elderly.

Introduction

The immune system serves as a critical arsenal for protection against bacterial, fungal, and viral infections; however, experimental data on immune changes with aging suggest a compromise in many of the parameters associated with normal immune cell function, termed 'immunosenescence’ [1], [2]. Advancements in modern medicine and nutrition have nearly doubled the human life expectancy from 40 to 80 years, yet our immune systems have not evolved to function properly into advanced age [1]. As a consequence, immunosenescence is inevitably part of the aging process, and leads to increased susceptibility to infection and suboptimal vaccine-induced immunity in the elderly population [3], [4], [5].

One of the greatest causes of morbidity and mortality in the elderly is the seasonal circulation of influenza viruses. Influenza is responsible for over 5 million cases of severe infection and 650,000 deaths each year, with the majority occurring within individuals aged 65 years and older [6], [7], [8]. Increased susceptibility and morbidity/mortality of influenza infections in this age group is largely a result of co-morbidities, as well as other immunocompromising factors, including cancer therapy or use of various medications [9], [10], [11]. However, immunosenescence is also a major contributing factor to influenza susceptibility, as it directly leads to a decline in optimal B cell- and T cell-mediated adaptive immunity induced by influenza virus vaccines [12].

Due to seasonal re-circulation, infuenza viruses exert repeated pressure on the adaptive immune system to generate effective B cell and T cell responses that clear virus and generate immunological memory against future exposures. Current influenza virus vaccines aim to induce protective B cell and T cell memory against the circulating viral strains but are largely ineffective, averaging only 47% effective during the 2018–2019 season [13]. This is due to the ability of influenza viruses to rapidly undergo antigenic drift, the process by which influenza mutates its viral genome in order to evade potent immunity elicited by the host [14]. As a result, seasonal vaccines must be constantly reformulated and are often mismatched to currently circulating strains. Protective immunity to influenza therefore relies on the generation of adaptive immune responses against antigenically drifted and novel viral epitopes each season, responses that are successfully elicited by seasonal influenza vaccines in young adults when vaccine strains are well matched with currently circulating strains. However, due to immunosenescence, complicated immune histories and other poorly defined factors, influenza vaccines remain ineffective in aged individuals [12], [15], [16], [17]. Consequently, the elderly are more susceptible to severe infection with influenza viruses [6].

Current research efforts are focused on understanding the mechanisms of immunosenescence and its impact on B cell and T cell function in response to influenza infection and vaccination. Here, we review our current understanding of the effects of immunosenescence on influenza-induced adaptive immunity, and explore potential solutions for developing effective influenza vaccines that circumvent the issues associated with immunosenescence and declined immune function in the elderly.