Immunosenescence and its Relevance to Vaccination

Immunosenescence covers all age-related changes that result in decreased immune function in the elderly — not restricted to senescence of immune cells alone but encompassing every immune system modification that characterises ageing.

Innate immunity is relatively little affected; adaptive (acquired) immunity is greatly affected. This is the most important organising principle.

Two components must be described together: immunosenescence (loss of specific responses) and inflammageing (excess non-specific inflammation). The paradox is basal immune stimulation with immune paralysis when a specific response is required. Changes in the Immune System With Age (Pathy's Table 2.3 — learn this list)

Thymic atrophy with loss of thymic hormones; decreased bone marrow production of B cells.

Decreased cell-mediated immunity and decreased delayed-type hypersensitivity.

Production of lower-affinity antibodies; increased autoantibodies.

Increased IL-6; decreased IL-2 and IL-2 responsiveness.

Accumulation of memory T cells (CD45); decreased proliferative response to mitogens.

Impaired macrophage function; NK cell number increases but cytotoxicity falls.

Toll-like receptor activation is diminished, producing dampened downstream cytokine responses when a real pathogen arrives.

Neutrophils show impaired phagocytosis, reduced ROS generation, reduced chemotaxis and decreased degranulation.

Dendritic cells show impaired phagocytosis, cytokine release and migratory capacity to lymph nodes. Impaired antigen-presenting cell activity is the hallmark of impaired innate AND acquired immunity in the elderly.

Efferocytosis — clearance of apoptotic cells and debris from airways — is impaired. Adaptive Immune Changes — The Basis of Vaccine Failure

Thymic involution reduces thymic output, so there are few naive T cells relative to antigen-experienced memory T cells. This directly hampers vaccine efficacy and the ability to respond to newly encountered pathogens.

Cytokine production by CD4+ and CD8+ T cells is impaired, and the CD4:CD8 ratio is altered.

B cells: dearth of naive B cells, and antigen-experienced cells lose function over time.

There is shrinkage of the antigenic repertoire of lymphocytes — "holes in the repertoire".

Chronic CMV infection drives clonal expansion of CD8 T cells; the resulting repertoire shrinkage predicts mortality in the very elderly (the immune risk phenotype).

Haematopoietic stem cell exhaustion is thought to be a major driver of immunosenescence.

Net result: increased prevalence of infection, increased malignancy, and increased autoimmunity, plus failure to clear pre-malignant cells, senescent cells and misfolded proteins. The Key Vaccine Mechanism — Most Examinable Single Fact Studies showing reduced efficacy of pneumococcal vaccination in older versus younger adults found NO difference in IgG levels. The explanation may be an altered IgM response leading to reduced opsonisation and phagocytosis of bacteria. Antibody QUANTITY is preserved; antibody QUALITY and function are lost.

Yearly influenza vaccination is indicated for ALL older patients — robust, frail, demented and end-of-life alike. More than 90% of deaths from pneumonia and influenza during epidemics occur in those aged 65 and over.

Vaccination reduces the risk of developing influenza by 50% and influenza mortality by 70%.

In nursing homes it is only 40% effective at preventing clinical illness, but is more effective at preventing pneumonia, hospitalisation and death. Vaccinating more than 80% of nursing home residents prevents outbreaks.

Adjuvanted influenza vaccine contains a substance that stimulates the immune response and enhances immunogenicity — particularly valuable in institutionalised elderly and those weakened by chronic disease. This is the direct clinical answer to immunosenescence.

Cocooning: vaccinating healthcare personnel in long-term care reduces respiratory infection incidence and overall mortality among residents, even when resident coverage is already high. Extend the offer to regular visitors and family.

Pneumococcal vaccine is less effective at producing protective antibody levels in older adults, but still reduces pneumococcal bacteraemia in high-risk patients.

CAPITA trial — PCV13 reduced the incidence of pneumococcal pneumonia by 45% in community-dwelling adults over 65. A large Japanese nursing home trial found marked reduction in mortality and pneumonia with PPSV23. Herpes Zoster — The Best Illustration of Overcoming Immunosenescence

Zoster incidence rises with age, affecting up to half of individuals aged 85 and over; post-herpetic neuralgia occurs in more than 40% of those over 60.

Zostavax (live attenuated) is only 30% protective. Shingrix (recombinant, adjuvanted) is 90% protective. A two-dose series is recommended from age 50, and those who previously received Zostavax should receive Shingrix.

Over half of tetanus cases occur in people aged 60 and over. Complete the primary series if history is uncertain, then booster every 10 years, with at least one dose given as Tdap.

SARS-CoV-2 vaccination is indicated for adults including those over 65, healthcare professionals, and family members in contact with older individuals.

Physical activity may ameliorate immunosenescence and thereby reduce age-related multimorbidity; Mediterranean diet promotes epigenetic rejuvenation (NU-AGE study).

Pneumococcal vaccination — age threshold lowered to 50 years. As of 23 October 2024, ACIP recommends that all PCV-naive adults aged 50 and over receive a single dose of a pneumococcal conjugate vaccine — PCV15 (Vaxneuvance), PCV20 (Prevnar 20) or PCV21 (Capvaxive). If PCV15 is used it must be followed by PPSV23 at least one year later, or after 8 weeks in the immunocompromised or those with a cochlear implant or CSF leak. Before October 2024, PCV was recommended only for all adults 65 and over plus those aged 19–64 with risk conditions. PCV21 was FDA-approved in June 2024. (MMWR 2025;74(1):1–8)

RSV vaccination — an entirely new vaccine for older adults. Three vaccines are FDA-approved: Abrysvo, Arexvy and mResvia. ACIP routinely recommends a single dose for all adults aged 75 and over, and a single dose for adults 50–74 at increased risk due to high-risk conditions, frailty, or high-risk living arrangements such as residence in a long-term care facility. RSV vaccination is currently a single dose only; revaccination is not recommended. Frailty and institutionalisation are now formal eligibility criteria — a direct clinical application of immunosenescence.

DANFLU-2 — high-dose influenza vaccine misses its primary endpoint. A pragmatic registry-based open-label randomised trial in Denmark across 2022/23 to 2024/25 enrolling 332,438 adults aged 65 and over, randomised 1:1 to high-dose or standard-dose inactivated influenza vaccine. The high-dose vaccine did not significantly lower hospitalisation for influenza or pneumonia. However, hospitalisation for any cardiorespiratory disease was lower with high dose (relative vaccine effectiveness 5.7%; 95% CI 1.4–9.9%). A prespecified secondary analysis of 43,881 participants with diabetes found high-dose vaccine associated with reduced cardiorespiratory, cardiovascular, heart failure, influenza and laboratory-confirmed hospitalisations irrespective of diabetes status. Exam message: enhanced-immunogenicity vaccines improve immune response and softer clinical endpoints, but a hard mortality benefit over standard dose has not been demonstrated. (NEJM 2025; JAMA Intern Med 2026)