What serious adverse events were reported in clinical trials of 2024-2025 updated COVID vaccines?
Executive summary
Clinical trials and large safety studies of updated COVID-19 vaccines and earlier mRNA products reported rare but serious events including myocarditis/pericarditis (especially in males 12–24), Guillain–Barré syndrome, cerebral venous sinus thrombosis, acute disseminated encephalomyelitis, and small excesses of some serious adverse events in randomized trials; the largest multinational cohort evaluated 99 million vaccinees and identified signals for several neurological and thrombotic events [1] [2] [3]. Independent re-analyses of randomized trials found an excess risk of serious adverse events of special interest with mRNA vaccines equivalent to roughly 12.5 per 10,000 vaccinated in combined trials and 18 per 10,000 in Pfizer’s trial [4].
1. What the clinical trials showed: randomized-trial signals
Randomized phase‑3 trials of the original mRNA vaccines reported few severe events overall but secondary analyses detected an excess of “serious adverse events of special interest” when Brighton Collaboration outcomes were applied: combined mRNA trials showed an excess risk of about 12.5 events per 10,000 vaccinated (risk ratio 1.43), and the Pfizer trial specifically showed an 18 per 10,000 excess (risk ratio 1.36) [4]. Trial reports still note that many common adverse events were transient and that the trials were not powered to detect very rare outcomes [5] [4].
2. Large observational surveillance: neurologic, thrombotic and cardiac signals
A multinational Global Vaccine Data Network cohort of 99 million vaccinated people compared observed vs expected rates for 13 adverse events of special interest and found increased observed-to-expected ratios for Guillain–Barré syndrome and cerebral venous sinus thrombosis after ChAdOx1 and a signal for acute disseminated encephalomyelitis after mRNA‑1273; the paper reports specific OE ratios (e.g., GBS 2.49; CVST 3.23; ADEM OE ratio 3.78 in one comparison) [1]. The BMJ summarized that study as identifying two rare neurologic events—transverse myelitis and acute disseminated encephalomyelitis—linked to COVID vaccination, while emphasizing those events were very rare [6] [1] [3].
3. Myocarditis and pericarditis: labeling and real‑world estimates
Regulators required updated warnings about myocarditis and pericarditis after mRNA vaccines and provided incidence estimates for the 2023–2024 formula: roughly 8 cases per million doses in people 6 months–64 years and about 27 cases per million doses in males 12–24 years during days 1–7 post‑vaccination, per FDA labeling updates [2]. The FDA’s action reflects both trial, postmarket and imaging follow‑up studies and shows cardiac inflammation remains the clearest rare, vaccine‑associated safety outcome acknowledged by regulators [2].
4. Balance of evidence: trials vs surveillance, causality limits
Clinical trials are large but underpowered for very rare outcomes; observational surveillance over tens of millions of doses identifies statistical signals but cannot alone prove causality because of confounding, differing background rates, and surveillance biases [5] [1]. The randomized‑trial reanalysis [4] and the GVDN cohort [1] reach overlapping but not identical conclusions: both find small excesses in serious outcomes, particularly for neurological and cardiac events, but magnitudes and implicated vaccines vary by study and method [4] [1].
5. What sources do and do not say about 2024–2025 updated vaccines
The multinational GVDN study (early‑2024) and regulator materials cite signals across vaccine platforms and across 2023–2024 formulations, but available sources do not provide a comprehensive, peer‑reviewed list of serious adverse events uniquely tied to the specific 2024–2025 updated vaccine formulations in randomized trials (available sources do not mention a definitive, public list specific to 2024–2025 randomized clinical trials) [1] [7] [2]. The FDA fact sheets and EUA/approval documents for updated 2024–2025 formulas note safety monitoring and state that trials did not reveal adverse events that establish a causal relationship for some manufacturers, while still updating myocarditis/pericarditis warnings [7] [2].
6. How to interpret risk in context
The absolute risks described in sources are very small: myocarditis estimates are in the tens per million; trial excesses of serious adverse events are on the order of 10–20 per 10,000 in secondary analyses [2] [4]. Regulators continue to weigh these small risks against benefits in preventing severe COVID‑19; FDA required labeling changes and ongoing follow‑up rather than product withdrawal, signaling judged net benefit but continued precaution [2].
7. Competing viewpoints and reporting caveats
Some systematic reviews of earlier trials concluded “no serious adverse events related to vaccination” in the trials they assessed, noting most events were unrelated or self‑limiting [8] [9]. That contrasts with secondary reanalysis and observational signals that identify small excesses in specific serious outcomes—differences driven by outcome definitions, analytic choices, and data scope [8] [4] [1]. Readers should note sources vary by design: randomized trial data, passive surveillance, and large linked‑database cohort studies each produce different types of evidence [4] [1] [2].
Limitations: this summary uses only the provided sources and does not attempt to adjudicate causality beyond what those studies and regulators state; for formulations released in 2024–2025, available documents emphasize ongoing monitoring rather than a single definitive trial‑level list of serious adverse events specific to those updated formulas [7] [2].