{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T09:20:01Z","timestamp":1774862401415,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Croatian Government","award":["KK.01.1.1.01.0006"],"award-info":[{"award-number":["KK.01.1.1.01.0006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Understanding the relationship between reactogenicity and immunogenicity after repeated BNT162b2 vaccination is critical for optimizing vaccination strategies. This study quantified their progressive dissociation across four vaccine doses. Methods: We conducted a prospective longitudinal cohort study among Croatian healthcare workers vaccinated with BNT162b2 from January 2021 to January 2024. Anti-SARS-CoV-2 IgG antibodies were measured at 16 timepoints using chemiluminescent immunoassay. Local (pain, erythema, swelling) and systemic (fever, fatigue, headache, myalgia, arthralgia, nausea) reactions were recorded for 7 days using FDA toxicity scale. Correlations were analyzed with Spearman\u2019s method and Bonferroni correction. Fourth-dose responses were predicted by exponential modeling. Results: Of 631 participants, 524 completed primary immunization, 418 received a third dose (173 with complete data), and 56 received a fourth dose (22 with complete paired data). Local reactions declined from 82.4% after the first dose to 42.9% after the fourth (p &lt; 0.001). Systemic reactions peaked at 44.8% after the second dose, then decreased to 26.0% after the third and 19.6% after the fourth. In contrast, median antibody levels rose from 9910 AU\/mL after the primary series to 29,002 AU\/mL after the third and 38,274 AU\/mL after the fourth. Correlations between reactions and antibody titer progressively weakened: r = 0.37 (95% CI 0.29\u20130.44, p &lt; 0.001) after the primary series, r = 0.08 (95% CI \u22120.07 to 0.23, p = 0.30) after the third, and r = 0.04 (95% CI \u22120.39 to 0.45, p = 0.86) after the fourth dose. Conclusions: Progressive dissociation between reactogenicity and immunogenicity was observed across four BNT162b2 doses. Booster doses maintain robust antibody responses despite reduced reactogenicity, reinforcing that minimal side effects are consistent with sustained humoral responses.<\/jats:p>","DOI":"10.3390\/vaccines14040305","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:22:36Z","timestamp":1774858956000},"page":"305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Progressive Dissociation Between Reactogenicity and Immunogenicity After Four-Dose BNT162b2 Vaccination: A 36-Month Longitudinal Study"],"prefix":"10.3390","volume":"14","author":[{"given":"Sanja","family":"Zember","sequence":"first","affiliation":[{"name":"Health Care Quality Unit, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, Mirogojska 8, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-3302","authenticated-orcid":false,"given":"Kristian","family":"Boduli\u0107","sequence":"additional","affiliation":[{"name":"Research Department, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, Mirogojska 8, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nata\u0161a Cetini\u0107","family":"Balent","sequence":"additional","affiliation":[{"name":"Department of Virology, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, Mirogojska 8, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alemka","family":"Markoti\u0107","sequence":"additional","affiliation":[{"name":"Research Department, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, Mirogojska 8, 10000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"},{"name":"Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8023-4314","authenticated-orcid":false,"given":"Oktavija","family":"\u0110akovi\u0107 Rode","sequence":"additional","affiliation":[{"name":"Department of Virology, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, Mirogojska 8, 10000 Zagreb, Croatia"},{"name":"School of Dental Medicine, University of Zagreb, Gunduli\u0107eva 4, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, September 11). 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