Cytomegalovirus Vaccines in Transplantation: History, Hurdles, and Hope

Cytomegalovirus (CMV) remains one of the most common and consequential pathogens in solid organ transplant (SOT) and allogeneic hematopoietic cell transplant (HCT) despite current prevention strategies. Even a partially effective CMV vaccine could reduce morbidity and mortality associated with CMV in SOT recipients (SOTr) and HCT recipients (HCTr), as well as decrease costs, toxicities, and the risk of antiviral resistance. Despite progress since the first CMV vaccine (Towne) was developed in the 1970s, no CMV vaccine has achieved regulatory approval. Differences in CMV epidemiology, host risk factors, and immune reconstitution between SOTr and HCTr, and heterogeneity in CMV vaccination goals across transplant populations, complicate the development of CMV vaccine candidates in transplantation. Incompletely defined immune correlates of protection and logistical barriers inherent to CMV vaccine clinical trial execution, such as unpredictable timing of transplantation and variable access to central laboratory monitoring, create additional challenges. This review describes the potential benefits of a CMV vaccine in HCTr and SOTr, summarizes prior trials of CMV vaccines in transplantation and the lessons learned, and provides a framework for overcoming historical barriers with innovative trial designs and validated biologic endpoints in the modern era of CMV prophylaxis to advance CMV vaccine candidates through clinical stages of development.