While access to COVID-19 vaccines remains a major global health challenge, vaccines are now widely available for American adults and adolescents. The great efficacy of COVID-19 vaccines has allowed for excellent individual protection against severe disease. However, immunocompromised patients, representing a population of several million Americans, are a notable exception. Severe COVID-19 infections among fully vaccinated, immunocompromised patients have raised significant concerns about the effectiveness of vaccines for this group. An observational study by Boyarsky, et al., validated these concerns: Of 658 patients who had received solid organ transplants, 46% developed no antibody response after two doses of mRNA vaccine.1

In an attempt to improve vaccine efficacy, a third vaccine dose was evaluated in two observational studies of patients receiving immunosuppressive medications after solid organ transplantation (including heart and heart-lung). Werbel, et al., studied patients who had received two doses of mRNA vaccine and were given a third dose of either mRNA or adenovirus vaccine.2 Among 24 patients with negative SARS-CoV-2 spike antibody titers after the second vaccine dose, 16 (67%) had no antibodies 2 weeks after the third dose. In a subsequent study, Kamar, et al., evaluated solid organ transplant patients receiving the Pfizer-BioNTech mRNA vaccine for all three doses. Among 59 patients with negative SARS-CoV-2 antibody titers after two vaccine doses, 33 (56%) remained without antibodies 4 weeks after the third dose.3

Conclusion: A three-dose COVID-19 vaccine regimen may provide protection for some immunocompromised patients who have not had adequate immunological response after two doses. Nonetheless, a majority will remain without antibody protection, and the risks of a three-dose regimen – including organ rejection and autoimmune disease exacerbation – have not been adequately studied. In the absence of robust herd immunity or more effective vaccination techniques, continued physical distancing, mask use, social restrictions, and vaccination of close contacts will remain essential for the health and safety of immunocompromised individuals.