In 2022, the antigenically divergent SARS-CoV-2 omicron variants (BA.1, BA.2, BA.4, BA.5) outcompeted previous variants and continued to cause substantial numbers of illnesses and deaths. We evaluated the safety and immunogenicity of the bivalent original/omicron BA.4/BA.5 Pfizer/BioNTech vaccine administered as a fifth dose to heart transplant recipients (HTxRs). We compared neutralization (using live virus assays) of SARS-CoV-2-infected cells in serum samples from HTxRs who had previously received 4 doses of the monovalent BNT162b2 vaccine with samples from HTxRs with breakthrough infection after 4 monovalent BNT162b2 doses. The fifth vaccination induced high neutralization efficiency against the wild-type virus and omicron BA.1, BA.2, BA.4, and BA.5 variants, with significantly higher neutralization efficiency being induced in HTxRs with breakthrough infection than in those without. Neutralizing titers in those with breakthrough infection were sustained above the level induced by the fifth dose in the uninfected. We conclude that the fifth bivalent vaccine is immunogenic, including to variants, with higher vaccine immunogenicity conferred by breakthrough infection. Nevertheless, the clinical protection conferred by the fifth dose is yet to be determined. The sustained neutralization responses in those with breakthrough infection support the notion of delaying booster in those with natural breakthrough infection.