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Review
. 2025 Dec;57(1):2477300.
doi: 10.1080/07853890.2025.2477300. Epub 2025 Mar 20.

Age-related changes in the immune system and challenges for the development of age-specific vaccines

T Mark Doherty  1 , Birgit Weinberger  2 , Arnaud Didierlaurent  3 , Paul-Henri Lambert  3
Affiliations
Review

Age-related changes in the immune system and challenges for the development of age-specific vaccines

T Mark Doherty et al. Ann Med. 2025 Dec.

Abstract

Background: A better understanding of how the immune system evolves with age and how vaccines work in older people has led to increasing focus on the development of vaccines aimed specifically at older age groups. We discuss strategies used to improve vaccine immunogenicity for older adults, focusing on licensed adjuvants.

Findings: With age-related immune decline (immunosenescence), older adults face increased vulnerability to infections and severe complications. Immunosenescence affects T-cell and B-cell populations and innate immunity, leading to reduced chemotaxis, cytotoxicity, and altered cytokine production. This contributes to inflammaging-low-grade, chronic inflammation linked to aging. However, immune responses vary due to genetics and life-long exposures, making chronological age an imperfect indicator of immune health. Vaccination remains key to prevention, yet immune dysfunction complicates vaccine efficacy. Strategies to enhance responses in older adults include mRNA vaccines, high-antigen content vaccines, intradermal administration, and adjuvants. mRNA COVID-19 vaccines generated strong immune responses in older adults, though lower than in younger groups. High-antigen content influenza vaccines have shown superior efficacy compared to standard vaccination. Adjuvants offer a well-established approach to boosting vaccine responses by enhancing innate immunity.

Conclusions: Of various strategies used to improve immunogenicity of vaccines for older adults, adjuvants have been the most consistently effective and practical. More recently, mRNA vaccines have also shown great promise.

Keywords: AS01; Adjuvant system; Vaccine; adjuvant; immunosenescence; inflammaging; older adults.

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Conflict of interest statement

MD is employed by and holds financial equities in GSK. AD received research grants from Sanofi, Moderna and GSK; consulting fees from Bioaster, Botanical Solutions and Sagitta; participated in Advisory boards for Sanofi; received honoraria for lectures from Sanofi, Roche and GSK; participated in a data safety monitoring board for AMC Biologicals. BW received payments or honoraria from Sanofi, GSK and MSD; participated in Advisory boards for Sanofi, GSK, MSD and Moderna; declares being a Member of Adult Immunization Board. AC received grants from GSK and Moderna; payments from GSK, Merck, Curevo, AbbVie Consulting, Moderna, HealthEd, Medical Journal of Australia and Eli Lilly; support for attending meetings from Moderna and GSK; participated in Advisory boards for AstraZeneca and Seqirus. The authors declare no other financial and non-financial relationships and activities.

Figures

Figure 1.
Figure 1.
Individual immunobiography. The figure shows the factors that can influence the heterogeneity of the immune response, contributing to an individual’s immune biography
Figure 2.
Figure 2.
Antibody titres and seroconversion rates at 28 days following influenza vaccination in adults ≥65 years of age: comparison of standard vaccines with high-dose and adjuvanted vaccines. Falsey et al. (2009) [72], Pepin et al. (2021) [73], Keitel et al (2010) [74], De Donato et al (1999) [97], Minutello et al (1999) [98], Seo et al (2014) [99] The figure shows a comparison of antibody titres and seroconversion rates induced by standard vaccines versus high-dose and adjuvanted vaccines
Figure 3.
Figure 3.
Mechanism of action of AS01. Amended from Cunningham et al. 2021 [111] The figure illustrates the mechanism of action of AS01, showing how QS21 stimulates macrophages to release IL-12 and IL-18, which in turn stimulate NK cells to release IFN. IFN attract dendritic cells which are stimulated by MPL. The dendritic cells then present antigen to both B-cells and T-cells. AS, Adjuvant System; DC, dendritic cell; IFN, interferon; IL, interleukin; MPL, 3-O-desacyl-4′-monophosphoryl lipid A; NK, natural killer
See this image and copyright information in PMC

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