Focusing on platforms that have advanced beyond phase I study, several vaccines have demonstrated varying degrees of protection against HCMV infection and/or disease in efficacy studies (Table 1). Early clinical trials of a live, attenuated HCMV vaccine in kidney transplant recipients demonstrated good protection against disease, but little effect on viral acquisition (161). Subsequently, an adjuvanted protein subunit vaccine based on the primary viral fusogen, gB, conferred partial protection against virus acquisition in seronegative adolescents and postpartum women in two distinct phase II trials (108, 109), one as a single center in postpartum women and the other as a multicenter trial in adolescent girls, which respectively demonstrated 50% and 43% efficacy of the gB vaccine. Furthermore, the gB vaccine reduced HCMV viremia and the need for antiviral therapy in HCMV-seronegative kidney and liver SOT recipients from HCMV-seropositive donors (95). While the gB vaccine was not licensed because its prevention of infection was modest and induction of neutralizing antibodies was limited, the efficacy result did not fully take into account the volume of the inocula of a transplanted organ, viremia levels, or related disease. Thus, a primary goal of HCMV vaccine development is to improve on the prior achieved efficacy and/or demonstrate higher efficacy using a virologic or disease outcome endpoint.

HCMV vaccines undergoing clinical trials

Other subunit vaccines based on envelope glycoprotein complexes are in clinical trials. The safety and immunogenicity of an enveloped virus-like particle vaccine expressing gB, with or without alum adjuvant, was evaluated in a placebo-controlled study in 125 participants (NCT02826798). The highest antibody titers were in the alum-adjuvanted 2.0 μg dose group (162). Several studies of an mRNA-based HCMV vaccine encoding gB and PC, mRNA-1647 (111, 163, 164), are in progress (Table 1), including a phase III efficacy study (NCT05085366), with results anticipated in 2025. An interesting expression platform using Hepatitis B SPYTag/SPYCatcher, and expressing the HCMV PC (NCT06145178), has been developed (Table 1). The manufacturer, SpyBiotech, recently completed participant enrollment in a phase I HCMV study of this vaccine, SPYVLP01, in 120 healthy adults, aged 18–50 years, over a six-month dosing schedule. Results have not yet been reported. Using the MVA vaccinia virus as vector carrying the pp65 protein plus IE proteins 1 and 2, a vaccine called Triplex showed promise against HCMV infection and reactivation in the allogeneic transplant setting in a published phase II trial (165). As a result, several new clinical trials have been ongoing or completed (see NCT06059391, NCT03354728, NCT05099965) that expand on the original design concept (166, 167). A multicenter phase II study of Triplex vaccine for “Control of CMV in Patients Undergoing Liver Transplantation” (COLT trial) is currently ongoing (NCT06075745). The V160 vaccine (described below) could also be considered for the transplant setting (168).

In the live, attenuated vaccine category, recent progress has been made. A whole-virus (but replication-incompetent) vaccine was recently evaluated in a phase II trial in women of child-bearing age. The vaccine (as noted above) is a DISC vaccine, V160 (145, 169, 170). The efficacy against primary HCMV infection in the phase II trial (NCT03486834) was 42% (168). Although the reported efficacy was suboptimal, case definition in this study was based on any detection of HCMV DNA in mucosal fluids in postvaccination follow-up, rather than the presence of systemic infection. Transient detection of viral DNA at mucosal sites may overestimate true acquisition events, resulting in an underestimation of vaccine efficacy (168). Furthermore, perhaps the endpoint of efficacy trials should be prevention of HCMV transmission to the fetus, not solely the prevention of maternal infection. It is currently unclear if clinical development of the DISC V160 vaccine candidate will continue.