How do side effects differ between first, second, and booster doses of Pfizer-BioNTech vs Moderna mRNA vaccines?
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Executive summary
Clinical trial-era data and early post-rollout monitoring showed both Pfizer-BioNTech (Comirnaty) and Moderna (Spikevax) mRNA vaccines cause similar patterns of local and systemic side effects that are generally mild-to-moderate and short-lived; many reports found slightly higher frequencies of some reactions after Moderna doses, and reactions were commonly stronger after the second dose than the first [1] [2] [3]. Booster doses produce side‑effect profiles broadly like earlier doses — mostly fatigue, headache, muscle pain and injection‑site pain — with some studies reporting that about a quarter to a third of mRNA booster recipients experienced symptoms that temporarily limited daily activities [4] [5] [6].
1. Early trial picture: second dose hits harder
Clinical-trial and early‑rollout accounts consistently reported stronger systemic reactions after the second dose of Pfizer and Moderna than after the first: trial participants often described fever, fatigue, headache and muscle aches after dose two, and regulators concluded there were “no specific safety concerns” that would block emergency authorization while noting common reactogenicity [1] [7]. Media summaries and trial fact sheets from the manufacturers quantified these patterns in different ways, but both vaccines showed the same qualitative pattern — a more vigorous short-term immune response after dose two [1] [3].
2. Moderna vs. Pfizer: small differences in frequency, not in kind
Multiple reports and observational datasets found more people reporting side effects after Moderna than after Pfizer in the early months of roll‑out. Local and systemic reactions were similar in type for both vaccines, but counts and percentages of reported symptoms (fatigue, headache, myalgia) were often higher in Moderna recipients in some datasets and news analyses [2] [3] [8]. Health‑system and news coverage emphasized that these are frequency differences in expected, usually transient reactions rather than qualitatively different harms [2] [3].
3. Boosters: similar symptoms, frequency varies by study and age
Booster doses of Pfizer and Moderna elicited the familiar reactogenicity profile — injection‑site pain, fatigue, headache, chills and muscle pain — and clinical booster trials reported many recipients experienced these symptoms but that they were self‑limited [4] [6]. Larger surveillance analyses found that a notable minority (around a quarter to nearly a third in some datasets) reported booster symptoms that interfered with normal activities; older adults tended to report fewer symptoms than younger adults [5] [6].
4. Serious adverse events and myocarditis: rare but monitored
Regulators and safety surveillance highlighted rare but serious events such as myocarditis and pericarditis after mRNA vaccination, particularly in younger males and typically within days of the second dose; these events are uncommon compared with the number of doses administered but are part of ongoing safety monitoring [9] [10]. Comparative reporting on myocarditis risk versus non‑mRNA boosters (e.g., Novavax) suggested lower myocarditis signals with non‑mRNA boosters, but mRNA boosters remain under active surveillance [11] [9].
5. Demographics and reporting bias change the appearance of differences
Analyses noted that women and younger people reported side effects more frequently (a CDC dataset reported 78.7% of adverse event reports from women in one early period) and that reporting systems and study populations influence apparent differences between vaccines [12] [8]. Media and community‑reporting platforms warned about reporting biases skewing comparisons; higher raw counts for one vaccine in passive surveillance can reflect differences in who got which vaccine and when [8] [2].
6. What the evidence does not say (limitations)
Available sources do not provide a definitive, head‑to‑head pooled estimate from a single, recent randomized trial directly comparing all dose‑by‑dose side‑effect rates between current, updated Pfizer and Moderna formulations; many papers and news stories draw on different periods (initial 2020–2021 trials vs later booster surveillance) and different vaccine formulations (original vs bivalent/updated), which complicates direct comparisons [13] [1]. Sources do not uniformly report precise per‑dose percentages across identical age groups and product formulations, so small numerical differences between brands should be interpreted cautiously [3] [2].
7. Practical takeaway for readers
Expect local pain plus systemic symptoms (fatigue, headache, myalgia) after mRNA doses; symptoms are usually greater after dose two and commonly similar for boosters. Some datasets found modestly higher frequencies after Moderna compared with Pfizer, but both vaccines’ side effects are overwhelmingly transient and predominantly mild-to-moderate; rare serious events (e.g., myocarditis) are being tracked by public health agencies [1] [2] [9]. For individualized risk/benefit decisions, consult up‑to‑date FDA/CDC materials and your clinician because up‑to‑date booster formulations and age‑specific data continue to evolve [13] [9].