Shingles and RSV vaccines with AS01 adjuvant reduce dementia risk

Shingles and RSV vaccines with AS01 adjuvant reduce dementia risk

New research finds that vaccines with the AS01 adjuvant can be improved to protect the aging brain from dementia, potentially redefining vaccine benefits beyond infectious disease protection.

In a recent study inNPJ vaccinesThe researchers demonstrated the short-term (18 months) protective effects of the AS01 adjuvant against the risk of subsequent dementia. This retrospective research utilized electronic health record (EHR) data from the Trinetx US Collaborative Network, which included more than 436,000 US adults, approximately half of whom received an AS01 adjuvant vaccine, while the remainder received a comparable non-AS01 adjuvant GLU vaccine.

Study results showed that participants who received AS01 adjuvant vaccines had a significantly lower risk of dementia over the following 18 months than participants who received the flu vaccine. This result remained robust regardless of vaccine type or participant gender, suggesting that the protective effects are primarily due to the adjuvant (AS01) and its potential neuroprotective immune responses. These results open a new frontier in preventative neurology and potentially position AS01 adjuvant vaccines as promising candidates for delaying or preventing dementia.

background

Flu vaccine as a comparator: The researchers specifically chose the flu vaccine for comparison because, like RSV, it affects the respiratory system and offers a relevant baseline while also lacking the AS01 adjuvant.

Dementia is an umbrella term for several age-related progressive cognitive declines that can severely hamper daily activities. Dementia is a global public health problem estimated to impact more than 57 million people (2021), the majority of whom are women. In today's aging world, dementia prevalence continues to rise, with projections suggesting that 139 million adults will have dementia by 2050.

Unfortunately, dementia remains without a cure, with current research efforts focused on identifying its risk factors and developing effective prevention measures. With this in mind, the current research group made an intriguing discovery in their previous work: Shingrix, a shingle vaccine, was associated with a lower risk of dementia compared to live anti-varicella-zoster virus vaccines.

The researchers hypothesized that this either meant the shingles were linked to dementia or AS01, an adjuvant that Shingrix had supplemented to improve its effectiveness (No AS01 in live vaccines), contributed to the observed reduced risk of dementia. However, these results were observational, raising questions about whether this benefit was derived from better viral protection (against shingles or varicella-zoster virus) or from interactions between the immune boosters.

About the study

Measurement of benefit: The reduced risk of dementia in additional time lived without a diagnosis: 87 additional days for RSV vaccines, 53 days for shingles vaccines, and 113 days for those both diagnosed within 18 months.

In the present study, researchers sought to isolate the impact of potential shingles-dementia associations by explicitly examining whether AS01 can modify the short-term risk of a dementia diagnosis. To do this, they compared people who received AS01 adjuvant vaccines with controls who received a flu vaccine without AS01.

The study compared the relative risk of a dementia diagnosis among members of each cohort over the following 18 months. Participant data were obtained from the US Trinetx Collaborative Network (USA). The electronic health record (EHR) dataset included 436,788 US adults (60+ years; majority between 70 and 73) who were administered Shingrix (n = 103,798), Arexvy (another AS01 adjuvant RSV vaccine; N = 35,938).

Of note, controls were sociodemographically and medically matched (66 variables) against cases via propensity score matching. Outcomes of interest included positive dementia diagnoses (International Classification of Diseases [ICD-10] codes) within 18 months of study enrollment/vaccine administration.

Statistical analyzes included the Kaplan-Meier estimator to calculate outcome measures, the generalized Schoenfeld approach for acceptance testing, and clinically meaningful estimates using a restricted mean time loss model (RMTL). The primary statistical comparisons were between these vaccine-defined cohorts, and analyzes were also stratified by gender.

Study results

Insight into the mouse model: The laboratory work cited in the paper suggests a specific component of AS01 (monophosphoryl lipid A or MPL) improved Alzheimer's disease pathology in mice and provides a potential biological pathway for the observed effect.

The study showed several compelling results. First, AS01 adjuvant vaccines demonstrated impressive short-term (18 months) protective effects against the risk of dementia. Participants who received AREXVY showed a 29% lower risk of dementia compared to controls, while those who received Shingrix showed an 18% reduction. Those who received both vaccines saw a 37% lower risk.

Remarkably, the protective effects of these vaccines were statistically indistinguishable, reinforcing support that the AS01 adjuvant, the only commonality between the vaccines, is a plausible explanation for the observed protective effect. Independent laboratory studies strengthen this idea, although the paper's authors note that the exact mechanisms remain speculative. They highlight that AS01 activates innate immune cells such as microglia, increasing pathogen disease and reducing inflammatory processes involved in Alzheimer's disease and the risk and progression of dementia.

Interestingly, the authors report a key limitation that may mean that the protective effect is even stronger than observed. The RSV vaccine group likely included some patients who received a non-AS01 vaccine.

In contrast, the hypothesized antiviral benefits of these vaccines on dementia risk (and more broadly, the potential associations between the diseases and dementia) are unlikely. These results remained robust after susceptibility testing and adjustment for vaccine type and gender. However, the authors emphasize that because the study is observational, unmeasured confounding factors may represent an association rather than a proven causal relationship and influence the results.

AAssociation between AS01 adjuvant vaccines and risk of dementia, negative control and zoster infection. Each point and BOLD number represent the restricted mean time ratio (RMTL) for the comparison between two cohorts, while horizontal lines and numbers in parentheses are 95% confidence intervals. RMTL ratios below 1 indicate that the risk is lower in the first cohort (e.g., first-line RSV vaccine recipients) than in the second (e.g., influenza vaccine recipients).b.Associations between AS01 adjuvant vaccines (compared to influenza vaccinations) and the risk of dementia in women, men and in the cohorts including those who developed dementia within the first 3 months after the race.

Conclusions

This real-world study adds to the growing evidence that AS01 adjuvant vaccines can protect brain health beyond their intended viral targets. With RSV and shingles vaccines showing significant reductions in dementia risk (29% for RSV and 18% for shingles), their combined effectiveness, rather than specific disease prevention, appears crucial to their holistic dementia predevelopment effects.

The results strongly support the need for future randomized clinical trials to confirm these effects and test AS01 boosters to prevent dementia. If confirmed, we may be able to use vaccine platforms not only for the control of infectious diseases, but as tools to delay or prevent cognitive decline, representing a significant paradigm shift in preventive geriatrics.

Sources: