Off-target (Unexpected) Benefits of Vaccines

“Given those ‘downstream effects,’ vaccines are key tools to promote healthy aging and prevent physical and cognitive decline.”

Stephania Maggi, geriatrician, National Research Council, Padua, Italy

“To expect the unexpected shows a thoroughly modern intellect.”

Oscar Wilde, Irish poet, playwright, and novelist

By definition, vaccines are biological agents that elicit an immune response to a specific antigen derived from a disease-causing pathogen. Since 1796 when Edward Jenner developed the first vaccine using cowpox to inoculate against smallpox, vaccines have helped suppress the spread of infectious diseases around the globe. According to the World Health Organization, global immunization efforts have saved at least 154 million lives over the past 50 years. Many public health authorities consider the on-target benefits of vaccines to be the biggest achievement of modern science.

In recent years, the “off-target benefits” (also called “heterologous effects” or “non-specific effects”) of certain vaccines have been in the news. In this week’s post, I discuss these vaccines and the “accidental” (unexpected) health advantages they provide.

Off-target benefits of vaccines. “Off-target benefits” of a vaccine refer to protective health outcomes of the vaccine that go beyond providing immunity against a specific disease or, to put it simply, outcomes that have little to do with the target (infection or disease) for which the vaccine was developed. There are now studies that show that the shingles, influenza, and Bacillus Calmette-Guerin (BCG) vaccines all provide health benefits beyond protection against the specific diseases they target.

Protection against dementia. Shingles is a severely painful neurological disorder caused by reactivation of varicella zoster virus (VZV)—the chickenpox virus. The condition afflicts about half of adults age 85 and older and vaccination is the only way to prevent it. The U.S. Centers for Disease Control and Prevention recommends two doses of Shingrix for all adults age 50 or older.

Shingrix is  90% effective in preventing shingles. It has also been shown to have “off-target benefits.” Multiple studies now show that Shingrix dramatically reduces the risk of Alzheimer’s disease—a neurodegenerative disease affecting more than 7 million Americans and for which there is little effective therapy.  (George, J., “Shingles Vaccine Tied to Dramatic Drop in Dementia Deaths,” MedPage Today, December 3, 2025).

In 2023, researchers at the University of Texas first reported that vaccines that target VZV, like Shingrix, also reduce the risk of Alzheimer’s disease. (Harris, K., et al., “The Impact of Routine Vaccinations on Alzheimer’s Disease Risk in Persons 65 Years and Older: A Claims Based Cohort Study and Propensity Score Matching,” Journal of Alzheimer’s Disease, August 7, 2023). A 2024 study from the University of Oxford showed a similar reduction in dementia in those who received Shingrix. (Taquet, M., et al., “The recombinant shingles vaccine is associated with lower risk of dementia,” Nature, July 25, 2024). (According to the findings, people who received the vaccine were 20% less likely  to develop dementia over the next seven years compared with those who remained unvaccinated.) And a 2025 Stanford-led study as well as a recent Canadian study reported similar findings.  (George, J. “Dementia and the Shingles Vaccine: What a New Study in Canada Found,” MedPage Today, January 26, 2026).

While there are a number of proposed mechanisms to explain this “off-target” reduction in dementia by a vaccine that reduces herpes zoster, the truth is the mechanism remains a complete mystery. Nonetheless, reducing your chances of developing Alzheimer’s—the potential “off-target benefit” of being vaccinated with Shingrix—should be an additional reason for all 125.5 million Americans over age 50 to get vaccinated against shingles.

Cardioprotective effects of vaccines. Influenza (flu) is a viral infection of the respiratory tract; the seasonal flu causes the deaths of approximately 50,000 Americans per year. Each year a new flu vaccine is developed based on predictions about the viral strains that are deemed most likely to cause flu in the upcoming season. Even though a vaccine’s overall effectiveness against seasonal flu is only about 50% to 60%, mounting evidence suggests the flu vaccines are effective against life-threatening influenza in older adults who have underlying heart disease.

In 2003, researchers at the University of Minnesota (Veterans’ Affairs Medical Center) published a landmark study showing that flu vaccinations significantly reduced the risk of cardiac disease in the elderly. (Nichol, K., et al., “Influenza Vaccination and Reduction in Hospitalizations for Cardiac Disease and Stroke among the Elderly,” The New England Journal of Medicine, April 3, 2003). (The study showed a 19% reduction in hospitalizations and a lowering of all-cause mortality by approximately 50%.) This study remains the strongest evidence for off-target cardiovascular benefits of flu vaccines.

Recently, Denmark provided more evidence supporting the off-target cardiovascular benefits of flu vaccines. Danish registry data from 2014-2025 suggests that prior flu vaccination is linked to a marked reduction (50% lower) in risk of acute myocardial infarction or stroke following breakthrough influenza infection among adults aged 40 years or older. (Croci, R., et al., “Influenza vaccination attenuates acute myocardial infarction and stoke risk following influenza infection: a register-based, self-controlled case series study, Denmark 2014 to 2025, Eurosurveillance, April 2026).

There are multiple proposed mechanisms for why influenza vaccination is beneficial to the cardiovascular system. But, again, the explanation is largely unknown. Nonetheless, the official recommendation for people with coronary artery disease, prior heart attack, heart failure, or other cardiovascular risk factors is to get an annual flu shot

BCG vaccine. The BCG vaccine was developed to treat tuberculosis (TB)—one of the world’s deadliest infectious agents claiming over 1 million lives globally each year. BCG vaccination prevents certain forms of TB in infants and therefore remains the most widely used vaccine in the world. (Globally, over 4 billion people have been immunized with BCG.)  

In addition, BCG vaccination has been associated with reduced all-cause childhood mortality, fewer respiratory tract infections and protection from some viral infections. BCG vaccine also is one of the oldest and most effective forms of bladder cancer immunotherapy. The off-target benefit of BCG in the treatment of bladder cancer is truly remarkable. (One fascinating aspect of BCG’s success in bladder cancer is it helped inspire modern cancer immunotherapy approaches, including checkpoint inhibitors.)

BCG vaccination is mainly used for non-muscle-invasive bladder cancer. A urologist places the vaccine in the bladder to stimulate cells of the immune system to attack the cancer cells. BCG significantly reduces tumor recurrence (meta-analyses show that BCG decreases recurrence risk by about 35-40%) and progression risk to muscle-invasive disease.

While the magnitude of these effects is debated, and the exact mechanism(s) underlying the immunotherapeutic effects of BCG are unknown, it appears that BCG vaccination is able to endow cells of the innate immune system, called monocytes or macrophages, with characteristics of “trained immunity,” that traditionally was considered to be associated with adaptive immunity (conferred by B and T lymphocytes). That is to say, BCG induces trained monocytes/macrophages to respond to unrelated stimuli, like cancer cells, in the bladder.

The off-target use of BCG for treatment of bladder cancer is being developed further. On May 28, 2026, the U.S. Food and  Drug Administration approved an immunotherapy-BCG combination for patients with high-risk bladder cancer. (Bassett, M., “FDA Oks Immunotherapy-BCG Combo for High-Risk Bladder Cancer,” MedPage Today, May 28, 2026). The approval was based on the results from “a phase III  POTOMAC trial, which showed that adding the immune checkpoint inhibitor to BCG induction and maintenance therapy significantly improved disease-free survival compared with BCG therapy alone.”

Benefits flow to the vaccinated. It is reassuring that a new survey of U.S. adults suggests that most Americans trust the work of vaccine scientists. In fact, the amount of trust in vaccine scientists (69%) was the same as it was for medical scientists (72%) and scientists in general (70%). (Dall, C, “Survey: Vaccine scientists held in high regard by most Americans,” CIDRAP News, April 27, 2026). One can only hope that this means that there will be an increase in vaccination rates in the U.S.

The primary reason to be vaccinated is for the “on-target” benefits—to be protected against a specific disease that can cause pain, suffering, long-term consequences, and even death.  The “off-target” benefits of vaccines are now, however, becoming more and more apparent. But, one only gets the benefit of a vaccine—be it  “on” or “off” target—if one is vaccinated.

Recent studies show that adults who received a high-dose flu shot had a significantly reduced risk for Alzheimer’s disease. (George, J.,  “Alzheimer’s Risk May Be Influenced by Flu Shots,” Medpage Today, April 6, 2026). Other research shows that both the respiratory syncytial virus vaccine and the diphtheria, pertussis, tetanus vaccine also provide protection from dementia. (Joi, P., “Eight vaccines linked to lower risk of dementia,” GAVI, April 28, 2026).  These studies suggest the “off-target benefit” of the vaccine—lowering the risk of dementia—is not virus specific.

In addition, there are new studies that show that the shingles vaccine may promote healthy aging by modulating biological systems beyond infection prevention. (Kim, J.K., Crimmins, E.M., “Shingles Vaccination May Promote Healthy Aging,” Vaccine Advisor, January 28, 2026). These along with the other “off-target benefits” mentioned in this post provide additional incentives for all of us to keep up-to-date on all vaccines.