Abstract Background Authorized COVID-19 vaccine platforms encode or deliver spike protein via distinct delivery architectures and excipient compositions. Among these, mRNA platforms use ionizable lipid nanoparticles (LNPs) with PEG-lipid excipients, while adenoviral vector platforms use free polysorbate 80 (PS80) as a stabilizing surfactant. Whether the tissue-specific adverse event profiles observed across platforms reflect antigenic or excipient differences has not been systematically evaluated. Methods We performed a comparative pharmacovigilance analysis combining literature-derived disproportionality estimates with original signal detection in VAERS OpenData (all reports through 29 May 2026; n = 1,924,924). Reporting Odds Ratios (ROR) with 95% confidence intervals were calculated for myocarditis/pericarditis/myopericarditis and for a combined POI/POTS/amenorrhoea endpoint across three COVID-19 vaccine platforms (Janssen, Moderna, Pfizer–BioNTech) and one free PS80 reference comparator (Gardasil). NVX-CoV2373 was excluded from the primary analysis because its Matrix-M adjuvant introduces independent membranolytic activity that prevents attribution of any signal to the PS80 micellar component alone. Platforms were classified by excipient architecture: free PS80 adenoviral and ionizable PEG-lipid LNP. Results Myocarditis disproportionality followed excipient architecture rather than antigenic content: PEG-lipid LNP platforms showed significant signal (Pfizer ROR 4.16, 95% CI 3.95–4.38; Moderna ROR 1.51, 95% CI 1.43–1.59), while the free PS80 adenoviral platform showed no signal (Janssen ROR 1.01, 95% CI 0.88–1.14), despite all three platforms encoding identical spike protein. The POI/POTS signal showed the inverse pattern: enriched in free PS80 platforms (Janssen ROR 1.42; Gardasil ROR 12.68) relative to PEG-lipid LNP platforms (Pfizer ROR 2.57; Moderna ROR 1.10). The POI/POTS:myocarditis ratio ranged from 0.62–0.73× in PEG-lipid LNP platforms to 1.41× in the free PS80 adenoviral platform and 71.47× in Gardasil. Interpretation We propose the Fusogenic Architecture Hypothesis: excipient supramolecular architecture — specifically, the capacity for endosomal membrane fusion — may be a major determinant of tissue-specific pharmacovigilance signals. Ionizable LNPs drive cardiomyocyte damage through endosomal rupture; free PS80 drives ovarian and autonomic damage through ApoE-mediated transcytosis into immunologically privileged compartments. This double dissociation is incompatible with spike-antigen-centered explanations and points to excipient architecture as an independent pharmacological variable requiring systematic evaluation in vaccine safety frameworks. Five falsifiable predictions are provided.
Añaños et al. (Sat,) studied this question.