What are the known serious adverse-event signals associated with RSV vaccines and how are they being investigated?
Executive summary
Post-licensure monitoring of RSV vaccines has flagged a handful of rare but serious adverse-event signals — notably Guillain–Barré syndrome (GBS), immune thrombocytopenia and thrombocytopenia, atrial fibrillation/cardiac events, preterm birth in pregnancy, and a safety signal for severe respiratory disease in some pediatric trials — and those signals are now the subject of active pharmacovigilance, epidemiologic study, trial pauses, and regulatory review [1] [2] [3] [4].
1. What serious-event signals have appeared in older adults and real‑world reports
Surveillance and trial summaries identify small excesses of neurologic and cardiac events in older recipients: multiple reports of Guillain–Barré syndrome (GBS) and rare immune‑mediated thrombocytopenia have produced strong disproportionality statistics in VAERS-based analyses for the two prefusion F protein vaccines, RSVPreF3 (Arexvy, GSK) and RSVpreF (Abrysvo, Pfizer), and regulators have noted a small increase in atrial fibrillation in the clinical trial populations of adults 60+ [1] [5] [3] [6].
2. Signals tied to pregnancy and perinatal outcomes
Analyses focused on maternal vaccination have repeatedly flagged signals for preterm birth and other pregnancy‑related complications: a VAERS disproportionality analysis reported an information component (IC) exceeding signal thresholds for preterm birth after RSVpreF in pregnant individuals (IC 2.18), and other studies have described pregnancy, puerperium and perinatal condition signals that merit active follow‑up [2] [1] [7].
3. Pediatric safety signal that halted trials and how it differs from post‑licensure findings
A distinct concern emerged in pediatric clinical development when Moderna reported higher rates of severe lower respiratory tract disease among vaccinated infants in early trials, prompting trial pauses and halting development of those pediatric mRNA candidates while FDA and sponsors reviewed the data; this represents an early trial safety signal rather than a post‑licensure VAERS signal [4] [8].
4. How strong the evidence is — signal versus proven causation
Current evidence is signal‑level and hypothesis‑generating: clinical trials largely showed similar overall serious adverse event rates between vaccine and placebo groups and were not powered to detect very rare events, while VAERS disproportionate reporting (ROR/BCPNN) and other real‑world analyses can identify statistical signals but cannot prove causality because of reporting biases, confounding and lack of denominator data [6] [5] [1] [9].
5. How investigators and regulators are following up these signals
Responses are multi‑pronged: passive surveillance (VAERS) and active systems (V‑Safe, CDC/FDA monitoring) continue to collect reports; formal disproportionality and time‑to‑onset analyses flag events for rapid review; epidemiologic studies and vaccine safety datalink investigations are being deployed to estimate incidence and adjust for confounders; trial data are reexamined and, where trial signals appear (as with Moderna’s infant signal), sponsors have paused studies and FDA has issued guidance and safety considerations for pediatric programs [1] [2] [6] [8] [4].
6. Competing interpretations, agendas, and what's missing
Manufacturers and regulators emphasize that benefits outweigh uncertain rare risks in older adults, pointing to robust vaccine efficacy and overall similar SAE rates in trials, while independent pharmacovigilance analyses urge continued caution and deeper study of specific outcomes like GBS and preterm birth; analysts note possible under‑ or over‑reporting in VAERS and call for active surveillance and controlled epidemiologic designs to quantify absolute risk — data that many sources acknowledge remain limited or inconclusive [3] [6] [1] [9].
7. Bottom line for policy and science
The signal list is short but consequential: GBS and immune thrombocytopenia, atrial fibrillation, preterm birth signals in maternal reports, and a pediatric severe‑respiratory‑disease signal in specific trials have triggered layered investigations — from enhanced surveillance and safety‑signal analytics to trial pauses and targeted epidemiology — but definitive causal estimates and risk stratification require prospective active surveillance and large observational studies that are currently ongoing or being planned [1] [2] [4] [9].