Enhancing longevity: the additional benefits of vaccination in older adults

Introduction

Vaccination is now seen as a whole-of-life approach to improving health by reducing many microbial diseases and their impact, including mortality. Some vaccines primarily improve quality of life without preventing infection (e.g. herpes zoster–shingles vaccination). There are an increasing number of vaccines available and recommended for older people.

Do vaccines have other benefits?

It was shown nearly 100 years ago that Bacillus Calmette–Guérin (BCG) vaccination reduces the risk of or the progression of some cancers¹ and more recently that this vaccine may reduce the risk of dementia.² Influenza and shingles vaccination has been associated with a reduced risk of cerebrovascular events and myocardial infarction.^3–5 The resilience of the evidence for the ‘off-target’ effects of vaccines currently recommended for older people remains under examination, as does the potential mechanism underlying these effects.

Vaccination and dementia risk

There is emerging evidence that the shingles vaccine might protect against dementia. In Wales, UK, receiving the live–attenuated vaccine reduced dementia incidence. 56% of those eligible received the vaccine. Over the subsequent 7 years, the risk of incident dementia (vascular or Alzheimer’s) was 28% lower (the hazard ratio, HR, was 0.72, with a 95% confidence interval, CI, ranging from 0.69 to 0.75), in those who received the vaccine as opposed to those who did not receive the vaccine. The risk was lower for vascular dementia (36%) than for dementia due to Alzheimer’s (19%). This reduction was not driven by failing to develop shingles versus developing it but was driven by being vaccinated.⁶

A subsequent analysis of the Welsh data utilised the fact that eligibility for the attenuated live herpes zoster vaccine was determined based on an individual’s date of birth. Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible to receive the vaccine. By using country-wide data on all vaccinations received, primary and secondary care encounters, death certificates and patients’ dates of birth in weeks, it was shown that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely 1 week too old to be eligible to 47.2% among those who were just 1 week younger. Apart from this large difference in the probability of ever receiving the herpes zoster live vaccine, there was no plausible reason why those born just 1 week prior to 2 September 1933 should differ systematically from those born 1 week later. Receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of 7 years by 3.5 percentage points (95% CI, 0.6–7.1; P = 0.019), corresponding to a 19.9% relative reduction in the occurrence of dementia.⁷

There have been other studies that have also strongly suggested that shingles (and other) vaccination reduces dementia risk.⁸ However, the existing data are limited and only refer to the live vaccine now discontinued in many countries in favour of a recombinant vaccine. Whether the recombinant shingles vaccine protects against dementia has also been examined. A natural experiment opportunity was created by the rapid transition from the use of live–attenuated to adjuvanted antigen vaccine. The recombinant antigen vaccine was associated with a significantly lower risk of dementia in the 6 years post-vaccination. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating into an additional 164 days lived without a diagnosis of dementia in those subsequently affected. The recombinant shingles vaccine was also associated with lower risks of dementia compared to two other vaccines commonly used in older people: influenza and tetanus–diphtheria–pertussis vaccines. The effect was robust across multiple secondary analyses, and present in both men and women but greater in women.⁹

Also, a recent US study aimed to determine whether recombinant zoster vaccine (RZV) immunisation was associated with a reduced risk of dementia diagnosis. This retrospective, observational, matched-cohort study of adults aged ≥50 years used data from the United States Optum de-identified Electronic Health Record data set, covering the period 1 October 2007–30 September 2023. A comparison cohort comprising adults vaccinated with the pneumococcal polysaccharide vaccine (PPSV23) was created to mitigate selection bias. Matched cohorts were then formed to compare those vaccinated with the attenuated live vaccine (ZVL) v. PPSV23, RZV v. PPSV23 and RZV v. ZVL, with neither comparison arm having been exposed to the comparator vaccine. Matching (1:1) used a propensity score generated with non-linear estimators based on 394 variables indicating past diagnoses, medication use, preventive health service uptake and healthcare service utilisation. Using the Nelson–Aalen estimator, the relative risk (RR) for dementia diagnosis (using International Classification of Diseases (ICD) −9 and −10 codes) was compared between the three matched cohorts at 3 and 5 years post-vaccination. Compared to PPSV23, ZVL significantly reduced 3-year (relative risk, RR, was 0.86, with 95% CI, 0.86–0.90; P < 0.0001) and 5-year dementia risk (RR = 0. 92; 95% CI, 0.89–0.95; P < 0.0001). RZV significantly reduced 3-year (RR = 0.76; 95% CI, 0.69–0.84; P < 0.0001) and 5-year dementia risk (RR = 0.80; 95% CI, 0.71–0.90; P < 0.0005), when compared to PPSV23. Compared to ZVL, RZV was also associated with a significant reduction of 3-year (RR = 0.73; 95% CI, 0. 60–0.89; P < 0.0005) and 5-year dementia risk (RR = 0.77; 95% CI, 0.64–0.92; P < 0.0005).²³

This effect may not be isolated to shingles vaccination. A meta-analysis of 17 studies of the effects of numerous vaccines (influenza, herpes zoster, Tdap, hepatitis A, hepatitis B, typhoid, BCG and rabies), including 1.8 million participants and followed for 3–20 years showed a 35% lower dementia risk (HR = 0.65; 95% CI, 0.60–0.71).¹⁰

Reducing cancer risk

Beyond the benefits of BCG vaccination on cancer progression, the best-known benefit of vaccination on cancer risk is the prevention of cervical cancer with human papillomavirus (HPV) vaccination. The basic concept of cancer prevention by vaccination involves harnessing our immune system to prevent cancer-causing viral infection through neutralising the oncogenic virus to prevent uptake by target cells, or to attack premalignant and latent or residual cancer cells that are clinically unapparent. Currently, safe and effective licensed vaccines against HPV and hepatitis B virus (HBV) prevent virus-associated cervical cancer and hepatocellular carcinoma (HCC) respectively. Other oncogenic viruses, such as human T cell leukaemia virus-1 (HTLV-1), Epstein–Barr virus (EBV) and polyomavirus, have recently seen renewed efforts related to vaccine development and also to evaluating these vaccines’ effect on virus-associated malignancies.¹¹ Vaccines targeted toward well-known and personalised tumour antigens are also under investigation. Although many of these benefits apply to mid- and early-life, and, although some of these vaccines were developed primarily to prevent cancer, similar benefits can be expected in older people.

Reduction of other diseases

The strongest evidence for the effect of vaccination on other diseases is cerebrovascular disease and myocardial infarction. Influenza vaccination has been shown to reduce overall cardiovascular mortality by 56% and ischemic stroke by 13%.^3,4 Shingles vaccination reduces myocardial infarction by 14% and ischemic stroke by 16%.⁵ Influenza and pneumococcal vaccination have been shown to reduce ischemic stroke by 33%, myocardial infarction by 48% and admissions to the coronary care unit by 55%.¹² Although these cardiac benefits are at least partly through reducing chest infections, so they are not strictly ‘off-target’ benefits, the reduction in stroke seems to be a genuine ‘off-target’ benefit.

Mechanisms

The additional benefits of vaccination could be explained by several factors. Concentrating on reduced dementia risk, there are several possible mechanisms. We could be seeing an anti-inflammatory effect or a reduction of the inflammatory response by reducing the severity of the infection. Inflammation around amyloid plaques is a process that is postulated to contribute to Alzheimer’s disease (AD), and vaccination may affect both peripheral and central nervous system inflammation.^13,14

Vaccination incites an immune response against the target microbe but may also incite the same response against other unwanted proteins central to AD pathology, including amyloid and tau – it may be acting as an ‘adjuvant’. Previous studies have also shown that influenza and BCG vaccines in animal models can enhance and maintain microglia activation, restore brain immune homeostasis and reduce amyloid-beta (Aβ) burden, ultimately reducing cognitive impairment.¹⁵

Microbes may induce AD pathology¹⁶ – it has been postulated that herpes viruses are linked with AD, mostly through herpes simplex virus type 1 (HSV1),¹⁷ and infection with herpes zoster virus (HZV) has been shown to reactivate HSV1 within neurons.¹⁸ Additionally, the gut microbiome is now recognised as a risk factor for AD and other dementias and vaccination might also affect this microbiome. More intriguingly, amyloid has antimicrobial effects and may be a response to infection. This might be mediated by TAR DNA-binding protein 43 (TDP43), a protein that is associated with AD and other dementias.

Other off-target effects of vaccination that could mediate these beneficial effects on dementia risk include heterologous lymphocyte responses, effects on innate immunity and stabilisation of the blood–brain barrier.

The beneficial effects of vaccination on stroke and cardiovascular events may be mediated by attenuation of vascular inflammation. Varicella zoster virus (VZV) may infect cerebral arteries, so vaccination against this may prevent or reduce this infection.^19,20 The effect of VZV on coronary arteries is more likely indirect, through systemic inflammation than through direct infection.

Conclusions

There are beneficial effects of vaccination beyond the primary aim of preventing infection by or reactivation of microbes. The one receiving the most attention currently is reduced dementia risk, and this seems to be particularly seen with the recombinant VZV antigen vaccine. However, other vaccines have also been shown to have favourable ‘off-target’ effects.⁵

These benefits of vaccination are comparable to addressing the 14 risk factors for dementia recently updated in the Lancet Commission on the prevention and management of dementia²¹ and of a similar magnitude to the benefits of disease-modifying therapies sach as ant-amyloid monoclonal antibodies.²² These results emphasise the importance of adults receiving their recommended vaccines, especially zoster vaccination. There appear to be a range of benefits from a greater ‘whole-of-life’ approach to vaccination of our increasingly ageing population and we need to move beyond an emphasis on childhood vaccination alone.