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"¡°All these associational studies suffer from the basic problem that people who get vaccinated have different health behaviors than those who don¡¯t,¡± said Pascal Geldsetzer, MD, PhD, assistant professor of medicine and senior author of the new study. ¡°In general, they¡¯re seen as not being solid enough evidence to make any recommendations on.¡±...

A natural experiment
But two years ago, Geldsetzer recognized a fortuitous ¡°natural experiment¡± in the rollout of the shingles vaccine in Wales that seemed to sidestep the bias. The vaccine used at that time contained a live-attenuated, or weakened, form of the virus.

The vaccination program, which began Sept. 1, 2013, specified that anyone who was 79 on that date was eligible for the vaccine for one year. (People who were 78 would become eligible the next year for one year, and so on.) People who were 80 or older on Sept. 1, 2013, were out of luck ¡ª they would never become eligible for the vaccine.

These rules, designed to ration the limited supply of the vaccine, also meant that the slight difference in age between 79- and 80-year-olds made all the difference in who had access to the vaccine. By comparing people who turned 80 just before Sept. 1, 2013, with people who turned 80 just after, the researchers could isolate the effect of being eligible for the vaccine.

The circumstances, well-documented in the country¡¯s health records, were about as close to a randomized controlled trial as you could get without conducting one, Geldsetzer said.

The researchers looked at the health records of more than 280,000 older adults who were 71 to 88 years old and did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold ¡ª comparing people who turned 80 in the week before with those who turned 80 in the week after.

¡°We know that if you take a thousand people at random born in one week and a thousand people at random born a week later, there shouldn¡¯t be anything different about them on average,¡± Geldsetzer said. ¡°They are similar to each other apart from this tiny difference in age.¡±

The same proportion of both groups likely would have wanted to get the vaccine, but only half, those almost 80, were allowed to by the eligibility rules.

¡°What makes the study so powerful is that it¡¯s essentially like a randomized trial with a control group ¡ª those a little bit too old to be eligible for the vaccine ¡ª and an intervention group ¡ª those just young enough to be eligible,¡± Geldsetzer said.


Protection against dementia
Over the next seven years, the researchers compared the health outcomes of people closest in age who were eligible and ineligible to receive the vaccine. By factoring in actual vaccination rates ¡ª about half of the population who were eligible received the vaccine, compared with almost none of the people who were ineligible ¡ª they could derive the effects of receiving the vaccine.

As expected, the vaccine reduced the occurrence over that seven-year period of shingles by about 37% for people who received the vaccine, similar to what had been found in clinical trials of the vaccine. (The live-attenuated vaccine¡¯s effectiveness wanes over time.)

This huge protective signal was there, any which way you looked at the data.¡±
By 2020, one in eight older adults, who were by then 86 and 87, had been diagnosed with dementia. But those who received the shingles vaccine were 20% less likely to develop dementia than the unvaccinated.

¡°It was a really striking finding,¡± Geldsetzer said. ¡°This huge protective signal was there, any which way you looked at the data.¡±"