What large-scale studies have tracked long-term safety of Pfizer and Moderna mRNA vaccines beyond five years?

1. What the available large studies actually measured and how far they reached

Randomized controlled trial follow‑up and large observational cohorts have provided multi-year but not beyond‑five‑year data. Moderna’s published follow‑up from the phase 3 COVE trial reports long‑term safety and effectiveness into later phases and booster periods, but the Nature Communications piece in the supplied materials describes long‑term outcomes through emergent variant waves rather than follow‑up exceeding five years ^[1]. A U.S. preprint examined twelve‑month all‑cause mortality after initial mRNA vaccination among Florida adults, explicitly covering a 12‑month window rather than multi‑year follow‑up beyond five years ^[2]. A large French epidemiologic analysis reported safety through March 2025 — “nearly five years after the start of the campaign” — and found no increased long‑term mortality, but that timeframe does not exceed five years for the entire vaccinated population ^[3].

2. What national surveillance systems add — and their limits

U.S. and other national monitoring systems (CDC’s Vaccine Safety Datalink, VAERS analysis and FDA surveillance) continue active surveillance and publish signal assessments such as myocarditis and Guillain–Barré syndrome rates. The CDC summary in the supplied sources emphasizes differential risks (for example higher GBS risk with Janssen versus mRNA vaccines) and ongoing monitoring, but does not present five‑plus‑year controlled cohort results for Pfizer or Moderna ^[5]. The FDA has warned that some cardiac MRI findings after vaccine‑associated myocarditis have uncertain long‑term significance and that studies are ongoing to determine whether those imaging changes predict durable heart disease; that statement underscores a knowledge gap rather than settled five‑year safety data ^[4].

3. Independent large cohorts and journal reports: mostly under five years

Recent peer‑reviewed and preprint cohort studies look at mortality and cause‑specific outcomes up to roughly one to several years. The French Epi‑Phare/JAMA analysis (reported in Le Monde) concluded no increased long‑term mortality through March 2025, a major population‑level reassurance covering most of the vaccination era but not conclusively beyond five years for all recipients ^[3]. The Florida study is a 12‑month cohort focused on all‑cause mortality after initial vaccination ^[2]. Moderna’s COVE trial follow‑up reports safety and effectiveness into booster periods but is not described in the supplied excerpt as exceeding a five‑year follow‑up window ^[1].

4. Scientific and regulatory caveats noted in the record

Regulators and investigators state explicit uncertainties. The FDA flagged that it “is not known if these heart MRI findings might predict long‑term heart effects of myocarditis,” and noted prospective studies are underway — again indicating ongoing work rather than completed five‑year outcome studies ^[4]. CDC ACIP and VSD analyses are cited for comparative short‑term adverse event rates (e.g., GBS comparisons), but those sources focus on signal detection windows (days to months) rather than multi‑year safety endpoints ^[5].

5. Competing perspectives and what is missing from current reporting

The sources present two consistent themes: large population analyses so far find no signal of increased long‑term mortality through early 2025 ^[3], and imaging and clinical follow‑up of rare vaccine‑associated myocarditis cases leave open whether any imaging abnormalities will translate into clinically important late outcomes ^[4]. What is not found in the provided reporting is any completed, large randomized or observational study that tracks vaccinated cohorts for more than five years post‑vaccination for comprehensive safety endpoints — “beyond five years” follow‑up is not documented in these sources (not found in current reporting).

6. Practical takeaway for readers and next milestones to watch

Current large studies and national surveillance up to 2024–2025 show continued reassurance on population mortality and on most short‑ to mid‑term safety signals ^{[3] [5] [2]}, but persistent regulatory flags about myocardial imaging and explicit promises of ongoing follow‑up mean definitive, large‑scale five‑plus‑year safety conclusions are not yet published in the supplied materials ^[4]. Watch for longitudinal cohort updates from Epi‑Phare, the Vaccine Safety Datalink, long‑term extensions of COVE and other phase‑3 trial cohorts, and formal FDA/ACIP reports — those are the places that would present any true beyond‑five‑year safety data when available ^{[1] [5] [3]}.