A Vaccine Against Dementia

by Gertrud U. Rey

The shingles vaccine is highly effective at preventing shingles, a painful rash caused by reactivation of varicella-zoster virus (VZV) – the herpes virus that also causes chickenpox. But what if this vaccine also prevented dementia? New data suggest that it just might.

The authors of a recent multinational collaborative research study used existing electronic health records in Wales to determine whether vaccination with the shingles vaccine Zostavax prevents dementia in older adults. The investigators applied the data to a regression discontinuity analysis – an experimental method that estimates the causal impact of an intervention by comparing outcomes of individuals who fit just above and just below a predetermined eligibility threshold. The threshold in this particular instance was a specific date. The investigators chose September 2, 1933, a date that determined whether a resident of Wales was eligible for vaccination with Zostavax. During the vaccination campaign, people born after September 2, 1933, were eligible to be vaccinated; and people born before this date, were not. Because it is unlikely that people born right before and right after this date would have any other major dissimilarities besides a small difference in age and a large difference in the probability of having received Zostavax, this strategy eliminates a large majority of confounding variables. Simultaneously, this method automatically generates an experimental population, many of whom were likely to be vaccinated, and a control population who were likely not vaccinated because they were not eligible. As it turns out, about 47% of vaccine-eligible participants had been vaccinated, and the vast majority of ineligible participants had not.

Data about whether participants received the Zostavax vaccine and other health outcomes were collected for 282,541 individuals born before or after September 2, 1933. The analysis revealed that members of the vaccine-eligible group were not only much less likely to get shingles, but they were also less likely to develop dementia over the course of a 7-year follow-up period. In fact, eligible individuals who were actually vaccinated with Zostavax had a 20% reduced probability of being diagnosed with dementia during the follow-up period. Although this protective effect was much stronger in women than in men, this difference may not necessarily be gender-specific, because women are generally twice as likely to develop dementia as men.

The authors also suggest a possible mechanism for how Zostavax might prevent dementia. VZV reactivations can cause cognitive impairment through neuroinflammation and other downstream effects. It is therefore likely that reducing viral reactivation by treating a shingles episode with antiviral medication may decrease the probability of a dementia diagnosis later in life. In line with this reasoning, the results of the study demonstrated that individuals who developed shingles but were treated with antivirals were less likely to be diagnosed with dementia a year or more after their shingles diagnosis compared to individuals whose shingles went untreated. The results also showed that individuals who experienced multiple rounds of shingles had a higher risk of developing dementia, suggesting that repeated reactivations of VZV replication increase the probability of dementia.

It is worth noting that in the United States, Zostavax was recently replaced with a newer and more efficacious VZV vaccine called Shingrix. It would be useful to know whether Shingrix has a similar effect in reducing dementia, considering that its mechanism of function is different from that of Zostavax. Zostavax consists of live-attenuated VZV that replicates in cells to a limited extent, thus triggering the recipient’s adaptive immune response to produce antibodies to various VZV antigens. In contrast, Shingrix is not infectious, but consists of a single viral surface protein, which acts as an antigen to induce production of antibodies that are specific to that protein. If Zostavax reduces dementia by preventing reactivation of VZV, then Shingrix should be even better at lowering the risk of dementia than Zostavax, considering that Shingrix is more effective than Zostavax at reducing VZV replication.

The correlation between infection with herpes viruses and onset of dementia later in life is well-documented, and I described a possible causative link between herpes simplex virus type 1 and dementia in a previous post. However, the study discussed here provides the strongest evidence so far that reactivation of a herpes virus may cause dementia, and it suggests a simple intervention that would be less expensive and far more effective at preventing or delaying dementia than existing pharmaceutical treatments. As a follow-up to these findings, clinical trials that evaluate the efficacy of Shingrix at preventing and/or delaying the onset of dementia should be conducted.