Adjuvanted Vaccine Against RSV Associated with Substantial Reduced Risk of Dementia
The adjuvanted RSV vaccine, in particular, was associated with a 29% reduction in the risk of dementia in the subsequent 18 months, a University of Oxford study found.
Vaccination with AS01-adjuvanted shingles (Shingrix) and respiratory syncytial virus (RSV) vaccines, either individually or combined, was associated with a reduced risk of dementia over 18 months, according to a large real-world study using US electronic health record data. Published in npj Vaccines, the study found that when compared with recipients of the influenza vaccine, people who received the RSV vaccine alone, shingles vaccine alone, or both vaccines had lower relative risks of dementia diagnosis that corresponded to 29%, 18%, and 37% additional time spent free of a diagnosis, respectively.
In terms of actual time spent dementia-diagnosis free, the percentages translate to 87, 53, and 113 days, respectively, for individuals diagnosed within 18 months of receiving a vaccination, Paul Harrison, BMBCh, DM, of the University of Oxford in England, and colleagues reported.
"No difference was observed between the two AS01-adjuvanted vaccines," including based on sex or baseline comorbidities," suggesting that the AS01 adjuvant itself plays a direct role in lowering dementia risk," Harrison and co-authors wrote.
The research builds on prior observational evidence linking shingles vaccination with lower dementia risk. Earlier studies had shown stronger associations with the AS01-adjuvanted recombinant shingles vaccine, ie, Shingrix, than with the live shingles vaccine (Zostavax).
"Two non-mutually exclusive hypotheses can explain the added protection provided by the adjuvanted vaccine compared to the live vaccine (which has no adjuvant)," the researchers wrote "Shingles might increase the risk of dementia, and the adjuvanted vaccine would therefore better protect against dementia through its greater efficacy; and/or the AS01 adjuvant might itself provide some protection against dementia."
Evidence for the relative contributions of both possibilities could support potential strategies for prevention of Alzheimer and other neurodegenerative diseases, they emphasized.
To test the hypothesis for the role of the adjuvant, Harrison and colleagues analyzed whether a second AS01-containing vaccine—Arexvy, used for RSV prevention—also conferred protection against dementia.
The analysis included more than 436,000 adults aged 60 years or older from the TriNetX database, a federated US EHR network. Cohorts were carefully matched for 66 covariates, the authors wrote, including age, sex, race, comorbidities, and other risk factors, with standardized mean differences below 0.1. Three vaccinated groups were compared to controls who received only the influenza vaccine: those who received the AS01-adjuvanted RSV vaccine (n = 35,938), the AS01-adjuvanted shingles vaccine (n = 103,798), and those who received both (n = 78,658). Flu vaccine recipients were chosen as the comparator group to control for health-seeking behaviors while isolating the potential contribution of AS01. Mean age across the 3 groups was 71. 5 years and approximately 63% of the cohort were women.
The study's index date, on or after May 1, 2023, corresponded with the FDA approval of the AS01-adjuvanted RSV vaccine. Exclusion criteria included a diagnosis of dementia, Parkinson or Alzheimer disease, and other neurogenerative disease before the index date or 3 months after that.
Each AS01 vaccine group showed a statistically significant reduction in risk of dementia diagnosis compared with flu vaccine controls. The greatest effect was observed in the dual-vaccine group, though the difference from single-vaccine recipients was not statistically significant, according to the analysis. Protective effects were consistent across men and women, and findings remained robust when including dementia cases diagnosed within the first 3 months of follow-up. Restricted mean time lost ratios were 0.71 (95% CI 0.61–0.83) for RSV vaccine only, 0.82 (95% CI 0.74–0.91) for shingles only, 0.63 (95% CI: 0.55–0.72, P = 4.7 × 10⁻¹²), respectively.
The authors examined whether the benefits could be explained solely by prevention of viral infection. While shingles and RSV have both been implicated as potential neurotropic contributors to dementia risk, the rapid onset of protection and absence of additive benefit from dual vaccination suggest a different mechanism. “If the adjuvanted vaccines exerted their protective effect via separate mechanisms, we would expect an additive protective effect… a pattern not observed here,” the authors wrote.
Instead, the researchers propose that AS01 itself may exert neuroprotective effects via immune modulation. AS01 includes monophosphoryl lipid A (MPL), a toll-like receptor 4 agonist, and QS-21, a plant-derived saponin. In animal models, MPL has been shown to improve Alzheimer pathology, and QS-21–containing formulations have been linked to enhanced cytokine responses, including IFN-γ, which may reduce amyloid plaque burden. These immune effects could be responsible for delaying or preventing cognitive decline in vaccinated individuals.
The study’s limitations include the use of retrospective EHR data, lack of confirmed dementia diagnoses, and incomplete identification of RSV vaccine brands, which may have diluted the observed effects. About 24% of the RSV group may have received a non-AS01 vaccine, suggesting that the actual benefit of Arexvy may be underestimated.
In conclusion, the authors report that both the AS01-adjuvanted shingles and RSV vaccines were associated with reduced dementia risk, and the shared adjuvant is a plausible contributor to this protection. They call for further mechanistic and longitudinal research to better understand the biological pathways involved and to assess whether these findings can inform dementia prevention strategies.
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