Solid organ transplant recipients have demonstrated a blunted immune response to standard 2‐dose vaccination against SARS‐CoV‐2. This study sought to determine the humoral response to heterologous booster vaccination (viral vector vaccine dose 1 and 2 + mRNA booster). Heart transplant recipients, aged 18 to 70 years of age who initially received two doses of the viral vector ChAdOx1 nCoV‐19 vaccine followed by a BNT162b2 mRNA booster were recruited. A detectable antibody response in the absence of prior SARS‐CoV‐2 was the primary outcome measured. This was defined as an anti‐spike titre of ≥0.8 U/mL on the Elecsys anti‐SARS‐CoV‐2 S immunoassay. A total of 80 heart transplant patients (mean age 49 ± 13 years, 28% female) were included. Blood samples were drawn at a median of 30 (IQR 28‐33) days after the BNT162b2 mRNA booster. The frequency of a detectable antibody response increased from 37.5% (
n
= 30) after dose 2 to 56% (
n
= 45) post dose 3 (
p
< 0.001). A non‐detectable antibody response was significantly more common in recipients with a shorter time interval from transplantation (
p
< 0.001), lower likelihood of cardiac allograft vasculopathy (p = 0.003) and in those prescribed a triple versus dual immunosuppressant regime (
p
= 0.009) and a tacrolimus versus cyclosporine basedregimen (
p
= 0.007). Despite heterologous prime‐booster vaccination 44% of this vulnerable population ultimately continue to have no detectable antibodies.
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