Receiving the recombinant shingles vaccine is associated with a lower risk of developing dementia among older adults who have recently spent time in a skilled-nursing facility. The findings suggest that this routine immunization might offer protective benefits against cognitive decline over a four-year period. This research was published in the Annals of Internal Medicine.
Shingles is a painful viral infection caused by the reactivation of the varicella-zoster virus. This is the exact same virus that causes chickenpox in childhood. The virus remains dormant in the nervous system and tends to reactivate in adults over the age of fifty or in people with weakened immune systems.
Previous clinical studies have linked a shingles infection to an increased risk of developing dementia later in life. Kaley Hayes is an associate professor in the Department of Health Services, Policy and Practice and the lead of the Pharmacoepidemiology and Regulatory Evidence Lab. She also serves as the associate director of pharmacoepidemiology at the Center for Gerontology and Healthcare Research.
Hayes explained the biological reasoning that prompted the research team to investigate this connection. “We examined the link between vaccination with Shingrix because shingles increases the risk of stroke and potentially just general inflammation in the brain,” Hayes said, referring to the brand name of the recombinant vaccine.
“There is a hypothesis that reducing activity of the virus that causes shingles (called herpes zoster), might therefore help to prevent brain inflammation that can damage brain health long-term,” Hayes said. Because of this hypothesis, scientists have wondered if preventing the viral infection might also protect the brain from cognitive decline.
Earlier observational studies provided evidence that an older version of the vaccine reduced dementia risk. “Prior studies in different populations that examined the older vaccine, Zostavax, did find a signal for dementia prevention,” Hayes said.
Zostavax is the brand name for the older live-attenuated vaccine, which contains a weakened, harmless form of the actual virus. That specific live vaccine is no longer available in the United States. In 2017, the United States Food and Drug Administration approved a new version known as the recombinant shingles vaccine.
Recombinant vaccines are made by synthetically producing specific pieces of a virus to trigger a strong immune response. This newer version is highly effective at preventing shingles in older adults. Because the newer vaccine works so well against the virus, there is growing interest in its potential to protect the brain.
“We wanted to use large, real-world data and a rigorous study design to find out if that signal exists for older adults in the US vaccinated with the newer, more effective vaccine,” Hayes said. Older adults admitted to skilled-nursing facilities represent a population at high risk for both shingles and new-onset dementia.
A skilled-nursing facility is an inpatient medical center that provides short-term rehabilitation after a hospital stay, as well as long-term care for those who need daily assistance. The authors recognized that admission to these facilities serves as a natural window for medical professionals to assess vaccine eligibility. They designed their study to see if giving the recombinant vaccine during or shortly after a facility stay would lower the rate of new dementia diagnoses.
To explore this relationship, the scientists used an analytical approach called a target trial emulation. In a traditional randomized controlled trial, researchers randomly assign participants to either receive a treatment or receive a placebo. Sometimes, running such a trial is not possible or ethical in frail populations.
A target trial emulation solves this problem by mimicking the design of a randomized experiment using existing observational data. The researchers analyzed electronic health records linked to Medicare claims for older adults across the United States. They focused on patients aged 66 or older who were admitted to a skilled-nursing facility between January 2017 and December 2022.
The final sample included 509,926 participants. The average age of the participants was 79 years, and about 63.6 percent of them were women. To be included in the analysis, the patients had to have no prior diagnosis of dementia and no previous doses of the newer recombinant shingles vaccine.
The scientists compared two treatment strategies using a statistical technique that creates duplicate records, or clones, of each person in the data. One artificial clone is assigned to a vaccinated group, and the identical clone is assigned to an unvaccinated group. If a person’s real-world medical data deviates from their assigned group, their artificial clone is censored, or removed from the ongoing analysis.
This complex statistical method helps balance the comparison groups and adjust for biases that typically plague observational research. The study defined the vaccinated strategy as receiving at least one dose of the recombinant shingles vaccine within twelve months of entering the nursing facility. The unvaccinated strategy meant receiving no doses during the entire study period.
The researchers tracked the participants for up to four years. They looked for new dementia diagnoses using medical billing codes from hospital stays, recurring physician claims, and pharmacy records for common dementia medications. They also tracked 57 different participant characteristics, including age, prior health conditions, medication use, and previous vaccinations.
Out of the more than half a million participants, 8,843 individuals received at least one dose of the recombinant shingles vaccine within the first year. This represents just 1.73 percent of the study population. Among those who were vaccinated, 87 percent received their dose after they were discharged from the facility.
The researchers found that the vaccinated group had a lower risk of developing dementia over the four-year follow-up period. Specifically, the four-year dementia risk was 18.8 percent for those who received at least one dose of the vaccine. In comparison, the risk was 24.6 percent for those who did not receive the vaccine.
This translates to an absolute risk reduction of 5.8 percentage points. On a relative scale, the vaccinated participants had a 24 percent lower risk of being diagnosed with dementia compared to their unvaccinated peers.
“Our study identified that as many as 1 in 17 cases of dementia might be prevented through shingles vaccination, though trials are needed to confirm these findings,” Hayes said. The association varied slightly depending on the characteristics of the patients. The protective effect tended to be weaker in men compared to women.
It was also less pronounced in individuals who had previously received the older, live-attenuated version of the shingles vaccine. It is important to understand that this study provides evidence of an association, rather than proving a direct cause-and-effect relationship. The findings are based on administrative claims data, which can sometimes contain coding errors or miss mild cases of cognitive decline.
The overall rate of vaccination in this specific population was also very low, which can complicate statistical comparisons. One specific limitation involves what scientists call healthy vaccinee bias. This concept suggests that people who choose to get vaccinated might also engage in other healthy behaviors, or they might generally be in better health than those who skip vaccines.
The researchers attempted to measure this hidden bias using negative control analyses. A negative control analysis looks for associations between the vaccine and completely unrelated health events. The authors tested if the vaccine was associated with outcomes like hip fractures or routine wellness visits.
Because a shingles vaccine cannot prevent a hip fracture, finding a link would suggest that the vaccinated group was simply healthier or more cautious overall. The negative control analyses did show signs that the vaccinated individuals were generally healthier, pointing to some residual confounding variables. When the researchers statistically adjusted their primary results to account for this underlying health difference, the protective association weakened.
Even in the most conservative adjustment, the vaccine was still associated with a 12 percent reduced relative risk for dementia. The exact biological reasons for this protective link remain a topic of ongoing scientific inquiry. The vaccine might reduce inflammation in the brain, or it might prevent the varicella-zoster virus from contributing to the buildup of toxic proteins associated with cognitive decline.
It is also possible that the vaccine generally modulates the immune system in ways that protect the nervous system. Future research should aim to confirm these findings through actual randomized controlled trials in nursing home settings. By randomly assigning vaccines in a controlled environment, scientists could definitively rule out healthy vaccinee bias.
Until then, this study suggests that administering the recombinant shingles vaccine could be a practical way to support cognitive health in older adults recovering from acute medical events. “The main takeaway is that the shingles vaccine is highly effective at preventing shingles, which is painful and can cause long-term health issues,” Hayes said. “And now there is evidence that something to prevent this physical ailment may help to keep our brain healthy, too.”
The study, “Dementia Risk After Recombinant Herpes Zoster Vaccination in Older Adults With a Recent Skilled-Nursing Facility Stay: A Target Trial Emulation,” was authored by Kaleen N. Hayes, Daniel A. Harris, Kevin W. McConeghy, Lexie R. Grove, Richa Joshi, Lisa Han, H. Edward Davidson, Preeti Chachlani, Thomas A. Bayer, Mriganka Singh, Yasin Abul, Frank DeVone, and Stefan Gravenstein.
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