An Open Letter to Acting Commissioner Diamantas: The FDA Needs a Regulatory Pathway for Vaccine-Based Dementia Prevention Trials Now

Dear Acting Commissioner Diamantas,

A paper published this month in Nature Medicine lays out one of the more urgent arguments I’ve read in clinical research in years: that large-scale randomized trials of live-attenuated shingles vaccination for dementia prevention are not just warranted, they are overdue. The authors ground their call in a growing body of epidemiological evidence linking varicella-zoster virus reactivation to elevated dementia risk, and they make a credible case that the live-attenuated Zostavax vaccine, not the recombinant Shingrix, may be the more relevant intervention to test for this specific purpose. I want to take that argument directly to you, because the scientific community can call for these trials all it wants. Without a coherent regulatory framework for repositioning an approved vaccine as a dementia-prevention intervention, those calls will stall in sponsor planning meetings and agency pre-submission conversations for years.

The evidence behind this question is no longer fringe. Large-scale longitudinal analyses of health records have established a consistent relationship between herpes zoster reactivation and increased dementia risk, with recurrent episodes carrying a higher risk than a single occurrence. Separately, research into the underlying mechanisms has identified that VZV reactivation can infect cerebral arteries, produce VZV vasculopathy resembling Alzheimer’s-type cerebrovascular disease, and generate amyloid-beta peptides in infected brain vascular cells. Herpes zoster itself carries a substantial burden in aging populations: standardized annual incidence rates in the United States ranged from 542 to 685 per 100,000 person-years between 2019 and 2021, rising sharply with age. The biological plausibility is credible. The epidemiological signal is consistent. What’s missing is the trial infrastructure to confirm or refute the prevention hypothesis at the scale the question demands.

The Regulatory Gap Nobody Wants to Name

Here’s where your agency’s framework creates a real problem. Zostavax already holds FDA licensure. Shingrix was approved in October 2017 for herpes zoster prevention in adults aged 50 and older, with pooled Phase III efficacy data from the ZOE-50 and ZOE-70 trials demonstrating strong protection in elderly patients. Both vaccines exist. Both have safety records. But repurposing either for a dementia-prevention indication would require a supplemental Biologics License Application, and the FDA’s existing pathway for new or expanded vaccine indications was designed for infectious disease endpoints with well-defined immunological correlates of protection. It was not designed for a neurodegenerative outcome measured over years in a cognitively normal aging population.

That design challenge is not trivial. To power a three-year prevention trial adequately using a standard cognitive outcome measure with a 25% treatment effect, some estimates put the required enrollment at more than 4,000 participants per arm. Running that kind of trial under the current sBLA framework, with no precedent, no pre-defined endpoint guidance for vaccine-based dementia prevention, and no clear endpoint agreement process from your Center for Biologics Evaluation and Research, is a prospect that will deter any sponsor who runs a realistic feasibility analysis. The Nature Medicine authors aren’t wrong that the trials are urgently needed. They just haven’t fully reckoned with what it will take to get them funded, designed, and submitted without agency clarity on what you’ll accept as evidence.

I want to raise one more complication you’ll need to address head-on. Live-attenuated vaccines carry contraindications in immunocompromised populations. Zostavax is contraindicated in patients with primary and acquired immunodeficiency states, including those with acute and chronic leukemia, and the risk of disseminated VZV disease in immunocompromised individuals is not theoretical. The population at highest risk for dementia, older adults in their seventies and beyond, overlaps substantially with populations on immunosuppressive therapies. Any large-scale prevention trial will need explicit participant selection criteria, safety monitoring frameworks, and stopping rules that your agency needs to have a position on before sponsors can responsibly proceed. Right now, that position does not exist in written guidance.

A Counterintuitive Problem With “Urgency”

The conventional assumption when researchers call for urgent trials is that the main obstacle is funding. Appropriations, NIH priority-setting, foundation resources. The regulatory pathway is treated as a technicality that gets sorted out once the money is in place.

That assumption gets the sequence wrong. Sponsors and academic trial networks will not commit serious resources to a multi-thousand-participant, multi-year dementia prevention trial if they do not know in advance whether the FDA will accept their primary endpoint, how it will evaluate a vaccine-based intervention against a non-infectious neurodegenerative outcome, or what evidentiary standard applies at the sBLA submission stage. The absence of a clear pathway does not slow these trials. It prevents them from starting. The NIH’s National Institute on Aging has issued calls for dementia prevention research. The first DUVAX Phase 1 trial, a randomized double-blind study of an adjuvanted Alzheimer’s vaccine enrolling up to 24 participants aged 40 to 65, has entered early-stage testing. But none of these efforts addresses the specific question raised in Nature Medicine: a large-scale repositioning of a licensed live-attenuated vaccine for a neurodegenerative prevention endpoint in older adults. That requires agency leadership, not just research ambition.

What I’m Asking You to Do

I recognize that you’re serving in an acting capacity, and I understand the institutional weight that carries. Precedent-setting guidance from an acting commissioner is politically complicated in ways that permanent appointees don’t always face. But the provisional nature of your role doesn’t diminish the authority of your office, and this is precisely the kind of scientific-regulatory alignment problem that your Center for Biologics Evaluation and Research can address through existing mechanisms without waiting for Senate confirmation of a permanent commissioner.

What the field needs from you is specific. First, direct CBER to convene a public workshop in 2026 with dementia researchers, vaccine trial sponsors, and biostatisticians to establish acceptable primary and secondary endpoints for vaccine-based neurodegenerative prevention trials. Second, issue draft guidance clarifying how a sponsor should structure a Type B meeting request for an sBLA seeking a dementia-prevention indication for an already-licensed vaccine. Third, address the live-attenuated safety question in writing: provide a framework for patient selection, exclusion criteria, and safety monitoring that trial designers can use without having to negotiate it from scratch in each individual pre-IND meeting. These are not sweeping policy reforms. They are the kind of technical clarity your agency produces routinely for novel drug development programs, and the dementia prevention field deserves the same.

The Nature Medicine authors are right that time matters here. Alzheimer’s disease alone affects an estimated 6.9 million Americans aged 65 and older, and that number will grow as the population ages. If a licensed vaccine already sitting in pharmacy freezers across the country carries genuine preventive potential for even a fraction of that burden, the cost of regulatory ambiguity is not a delayed approval. It’s a decade of delayed evidence while patients develop dementia that might have been prevented. That is an outcome your office has the standing to help prevent, starting with a workshop announcement and a draft guidance document. I hope you will.

With respect,

Moe Alsumidaie
Editor-in-Chief, Clinical Trial Vanguard

References

1. Nature Medicine — “Why large-scale randomized trials of live-attenuated shingles vaccination for dementia prevention are urgently needed”
2. ResearchGate — “Varicella-zoster virus reactivation and the risk of dementia”
3. ResearchGate — “Mechanisms by which varicella zoster virus contributes to Alzheimer’s disease pathologies”
4. PMC — “Herpes zoster incidence rates and healthcare costs in aging populations, 2019–2021”
5. NITAG Resource — “Statement on the Clinical Use of Zoster Vaccine in Older Adults in Australia” (Zostavax contraindications)
6. Journal of the Pediatric Infectious Diseases Society — “FDA Regulatory Pathway for Vaccine Indication Expansions”
7. American Health and Drug Benefits — “Shingrix (Zoster Vaccine Recombinant): FDA Approval and Phase III Efficacy Data”
8. PMC — “Sample size and statistical power requirements for dementia prevention trials in cognitively normal elderly populations”