BackgroundDefining immune correlates of protection against COVID‐19 is pivotal for optimizing the use of COVID‐19 vaccines, predicting the impact of novel variants on clinical outcomes, and advancing the development of immunotherapies and next‐generation vaccines. We aimed to identify vaccine‐induced immune correlates of protection against COVID‐19‐related hospitalizations in a highly vaccinated heart transplant (HT) cohort.MethodsIn a case‐control study of HT recipients vaccinated with the BNT162b2 vaccine, patients were prospectively assessed for vaccine‐induced neutralization of the wild‐type virus, and the Delta and Omicron BA.1, BA.2, BA.4, and BA.5 variants. Comparative analyses with controls were conducted to identify correlates of protection against COVID‐19 hospitalization. ROC analyses were performed. Primary outcomes were COVID‐19 hospitalizations and severity of SARS‐CoV‐2 breakthrough infection.ResultsThe study cohort comprised 59 HT recipients aged 58 (49,65) years with breakthrough infections after three or four monovalent BNT162b2 doses; 41 (69.5%) were men. Thirty‐six (61%) patients with COVID‐19 were hospitalized; most cases were non‐severe (58, 98%). For hospitalized (vs. non‐hospitalized) COVID‐19 patients, vaccine‐induced neutralization titers were significantly lower against all SARS‐CoV‐2 variants (p < .005). Vaccine‐induced neutralization of the wild‐type virus and delta and omicron BA.1, BA.2, BA.4, and BA.5 variants was associated with a reduced risk for COVID‐19‐related hospitalization. The optimal neutralization titer thresholds that were predictive of COVID‐19 hospitalizations were 96 (wild‐type), 48 (delta), 12 (BA.1), 96 (BA.2), 96 (BA.4), and 48 (BA.5).ConclusionsBNT162b2‐vaccine‐induced neutralization responses are immune correlates of protection and confer clinical protection against COVID‐19 hospitalizations.