SARS-CoV-2 has infected a large fraction of the human population. Currently, most individuals have developed immunity either through vaccination or natural infection. Despite this, SARS-CoV-2 booster immunizations are still recommended to reduce the risk of reinfections, but there is still limited understanding on how different booster vaccine platforms influence antibody responses. We conducted immunological studies in mice to evaluate the boosting effects of different vaccine platforms on antibody responses. C57BL/6 mice were first primed with an adenovirus serotype 5 (Ad5) vaccine expressing the SARS-CoV-2 spike protein. The mice were then boosted with the same Ad5-based vaccine (homologous boosting) or with a protein-based vaccine (heterologous boosting). Interestingly, the heterologous regimen (Ad5 prime + protein boost) elicited superior antibody responses, relative to the homologous regimen (Ad5 prime + Ad5 boost). Similar potentiation of antibody responses was reported when mice were primed with poxvirus or rhabdovirus vectors and then boosted with protein. These findings highlight a potential advantage of protein booster immunizations to potentiate humoral immunity.