Adult Vaccination, Getting to Know Their Nonspecific Effects

We are writing to the Journal of Gerontology to thank them for the publication of “Lower risk for dementia following adult tetanus, diphtheria and pertussis (Tdap) vaccination” by Scherrer et al. (1). The authors found in 2 different cohorts, an overall reduction of dementia of 42%. This was in spite of differences in gender, socioeconomic status, and medical histories. The authors accounted for confounding factors by a reweighting of the data and noted the limitations of this type of study. We can now add a number of immunizations that have been reported to reduce dementia, which is mostly accounted for by Alzheimer’s disease (AD). These include in addition to DPT, tetanus or diphtheria alone, anti-influenza, anti-pneumonia, and Bacille Calmette–Guérin (BCG), the 100-year-old antituberculosis vaccine (2–5). Shingles is also reported as “under review” (1). One thinks of a specific vaccine for a specific disease, but these reports aim at the “nonspecific effects” (NSE) of these vaccines.

In the case of children, as early as 1931, BCG was noted by Calmette—the “C” of BCG, to act on a number of conditions other than tuberculosis, reducing infant mortality by 50% (6–8). However, very little attention has been paid to the NSEs of adult vaccines. An exception has been the influenza vaccine. An effort to evaluate its NSE was found to have a considerable effect on reducing the rates of heart failure (9). Another adult study of Giamarellos-Bourboulis et al. (10) was impressive, where hospitalized older at-risk patients were offered on discharge to enter a double-blind BCG vaccination study. Followed up for 1 year, a very significant reduction was noted in recurrence of pulmonary infections.

BCG as Immunotherapy in AD

In the pre-COVID-19 era, Ristori et al. (11) had already published studies on BCG widening its protection to 2 autoimmune diseases: type 1 diabetes (T1D) and multiple sclerosis (MS). Klein (12) also reported the relationship to T1D when he examined early vaccination with BCG and its inverse correlation with T1D in female inductees in the Israeli army and in Swedish youth. These studies encouraged our group to look at AD where inflammation is central. In patients with superficial bladder cancer, BCG was instilled into the urinary bladder repeatedly and in large doses. This older at-risk population was followed for the incidence of AD (3). The Hadassah University Hospital, where the study was carried out, has a low attrition rate, covered by electronic health records since 2000. It serves approximately 1.5 million people. The hospital had a follow-up on the study population for 18 years. The BCG recipient group was found to have 80% less risk to develop AD than the control group given other therapies. Supportive data have just been published from 2 sources other than Hadassah (5). The Clalit Health Services, Israel’s largest Health maintenance organization, covers approximately 4.5 million members—half of the Israeli population. With its patient population of older than 75 years of age treated with BCG, approximately 32% had less risk of developing AD than the control group treated by other methods. The longest follow-up was 18 years with a mean time of 7.5 years. In the University of California, Los Angeles Health System, its associated Discovery Data Repository contains clinical records for more than 1.5 million patients. Although the period of follow-up was only a year, 3.5% of the untreated population developed AD while less than 1% of the BCG treated group was diagnosed as AD. In these studies, there was a concern of bias including that of “frailty,” but it was not found to be different in the BCG treated or not treated control groups.

What Do We Know About the NSEs of Adult Vaccinations and Should Their Vaccination Be on the Public Health Agenda?

Until recently, massive use of a vaccine has not been given to the adult population in high-income developed countries. The exception was for the prevention of influenza and to that, we can now add the anti-COVID-19 vaccines, which will certainly add up to billions of vaccine recipients. Unfortunately as yet, the NSEs are not being routinely recorded. Before the development of specific anti-corona vaccines, more than 20 clinical trials were launched of BCG given to protect COVID-19 caregivers. If these studies, which were generally designed for short-term results, can be prolonged to examine later comorbidities, such as respiratory infections, AD, Parkinson’s, MS, lupus, and inflammatory bowel disease, a valuable “big data” base for the NSEs of adult vaccination could be established. If this profile of benefits or lack thereof is determined, policy decisions would have a basis in plentiful evidence. Kelley et al. (13) writing in 2015 found that the cost in the previous 5 years of treating AD to the health system and including the families’ expenditures was more than the burden of cancer and cardiovascular disease together. All attempts to treat established AD or even to slow its course have failed thus far. When one considers the expected growth globally of the older than 65 population, it seems a major effort in the direction of understanding the effects of adult vaccination and the policy for its future application is especially worthwhile.

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