A vaccine against cytomegalovirus: how close are we?

The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.

HCMV infection is the most common congenital infection globally and the most important infectious cause of pediatric disability, including sensorineural hearing loss (SNHL), and yet the virus is ubiquitous in the human population (10, 11), with seropositivity ranging from 60% of adults in industrialized countries to close to 100% of adults in low- and middle-income countries (12, 13). In healthy individuals, an initial HCMV infection may cause a mononucleosis-like syndrome (14, 15), but primary infections are very often asymptomatic/subclinical or may present simply as an undifferentiated febrile ailment (14). Rates of acquisition of infection are increased in breast-fed infants (16); in toddlers (and parents of toddlers) attending group day care (17–21); and in sexually active adolescents and young adults (22–24). It is rare for breast milk–acquired infections to cause disease, with the exception of that in premature infants, in whom acquisition of HCMV from milk can produce a “sepsis syndrome” (25), characterized by thrombocytopenia, neutropenia, and hepatitis. Although the link to adverse neurodevelopmental sequelae for these postnatally acquired infections in premature infants is unproven, there are studies suggesting that such infections may confer an increased risk of SNHL (26).

Like other herpesviruses, HCMV can enter a period of latency after the initial infection and reactivate episodically over the life course (27, 28). During reactivation, viral shedding at mucosal services is common but virtually always asymptomatic. Important sites of latency include the progenitor cells of the myeloid leukocytic lineage, such as CD34⁺ cells and their CD14⁺ derivatives (29). HCMV reactivation and attendant disease are particularly common when the host immune system is suppressed, such as in HSCT recipients (30, 31), SOT recipients (32), and in individuals with other (often iatrogenic) sources of immunosuppression (28, 33). These distinct clinical scenarios, and the implications of these manifestations of infection for vaccine development, are considered in more detail below.

Global studies have consistently highlighted the potentially debilitating consequences of intrauterine HCMV transmission, also referred to as vertical transmission. cCMV, which occurs in up to 1 in every 200 live born infants, is a pervasive global cause of childhood hearing loss and neurodevelopmental disability as well as other conditions such as hepatitis and seizure disorder. Up to a quarter of congenitally infected infants will have a life-long disability due to fetal infection (34, 35). In the US alone, it is estimated that 20,000 such infections occur annually, with up to 5,000 of these infections resulting in disabilities (36), costing the US health system up to $4 billion annually (37, 38). cCMV is the most common infectious cause of SNHL, estimated to be the cause of 25% of all childhood hearing loss by age 4 years (39). Furthermore, cCMV infection has recently been associated with an increased risk of acute lymphoblastic leukemia (40–43), potentially making childhood cancer prevention another reason for the urgent need for an HCMV vaccine.

As noted above in the Introduction, preconception maternal immunity partially protects infants from vertical HCMV transmission, as demonstrated by a higher rate of congenital transmission and fetal injury after viral infection in seronegative (i.e., newly infected) women compared with seropositive (i.e., infected prior to pregnancy) women (44). However, preconception seropositivity does not confer complete protection against reinfection and subsequent transplacental transmission, and most cCMV infections occur in the setting of preexisting immunity (45). Since the prevalence of cCMV is directly, and not inversely, proportional to the seroprevalence of HCMV in the reproductive population, there is a disproportionate impact of cCMV in children from low-income and underrepresented populations (46–48). This “apparent paradox” (49) of maternal serostatus as a risk factor for cCMV suggests that ultimately the control of cCMV will require immunization of seropositive women, toward the goal of boosting preexisting immunity. Previous consensus panels have identified prevention of maternal infection as the yardstick for licensure of a cCMV vaccine (50), but little attention has been given to the issue of vaccinating seropositives. Arguably, a cCMV vaccine could have its most substantial public health impact in low- and middle-income countries, where the seroprevalence of CMV and therefore the prevalence of cCMV is at its highest. These issues are considered in greater detail later in this Review.

For the SOT and HSCT settings, a variety of benefits could be achieved through licensure of a vaccine for HCMV. HCMV replication following SOT and HSCT has a broad impact on transplant outcomes. Infection contributes to end-organ disease (viremia, pneumonitis, enteritis, and retinitis) and has secondary effects such as increased risk of opportunistic fungal infections, graft-versus-host disease, and graft failure (51). HCMV-related complications have been estimated to increase health care costs by up to 49% for SOT recipients (52). In contrast to maternal-fetal HCMV transmission, where nucleoside antivirals are relatively untested (53, 54), high-risk populations have benefited from the advent of antivirals, with profound effects on HCMV-related morbidity and mortality. Ganciclovir and valganciclovir are currently the drugs of choice for the prevention and treatment of HCMV in HSCT and SOT recipients (32, 55–58). However, the use of antivirals is limited by significant toxicities, including myelosuppression, predominantly neutropenia, and acute kidney injury as well as the development of drug-resistant viral strains (51). This provides a powerful rationale for the development of a HCMV vaccine strategy for SOT and HSCT recipients.

In addition to the potential association between cCMV and pediatric leukemia (40–43), acquisition of HCMV infection over the life course has been putatively linked to several adult-onset cancers, including glioblastoma multiforme, breast cancer, colon cancer, and prostate cancers (59, 60). HCMV-seropositive status is associated with an enhanced risk of all-cause mortality (61, 62) and with cardiovascular diseases, including atherosclerosis (63). There is a past history of HCMV infection as a cofactor in the pathogenesis of disease due to Mycobacteria tuberculosis (64–66) and also as a cofactor in the progression of HIV-associated opportunistic infection, including meningitis caused by Cryptococcus neoformans (67). Latent CMV infection exerts a major influence on the immune system during aging, potentially contributing to immunosenescence and the pathogenesis of age-related diseases (68). There are some studies suggesting that HCMV seropositivity reduces the immune response to influenza (69) and COVID-19 (70) vaccination. Patients with critical illnesses requiring intensive care unit (ICU) admission have an increased likelihood of adverse outcomes, including death, if they are HCMV seropositive, which correlates with the magnitude of DNAemia that occurs during their ICU hospitalization (71, 72). For all of these reasons, routine universal immunization against HCMV may confer a broad benefit on human health.

HCMV is a member of the human Herpesviridae, a family of 8 related viruses (73) that share basic genetic (double-stranded DNA genomes), morphologic (enveloped virus particles), and epidemiologic (human-to-human transmission) features. Of the human Herpesviridae, HCMV has the largest and most complex viral genome, encoding, as noted above, many homologs of human immune modulation genes (74). The HCMV genome undergoes extensive intra- and intergenic recombination, contributing to a high mutational frequency akin to that of an RNA virus (75–77). This resulting extensive level of strain diversity contributes to the phenomena of reinfection and complicates vaccine development.

Immunity against HCMV is complex, including neutralizing and nonneutralizing effector antibody responses as well as NK and T cell functions. It is unknown why reinfections occur despite preexisting immunity; HCMV strain variation, the quantity of viral inoculum upon exposure, and the capacity of the virus for cell-cell spread may all play roles in enabling reinfection. HCMV vaccine development is complicated by the fact that immunity conferred by natural infection is, at best, imperfect. HCMV encodes a plethora of immune modulation genes that interfere with the host response to infection. These include gene products that downregulate MHC class I molecules on the cell surface, interfering with the CD8⁺ T cell response (78); proteins (79–81) and a microRNA (82) that modify the NK cell response; homologs of human cytokine genes, including IL-10 (83–85); chemokines and G protein–coupled chemokine receptors that modulate the inflammatory response (86, 87); and FCγ IgG receptors that interfere with antiviral host immunoglobulin functions (88). As noted above, HCMV establishes latency (28) and reactivates frequently over the life course, particularly in the context of intercurrent illness or immune suppression (71). These factors contribute to the phenomena of reinfection, which can occur in pregnant individuals (45) or in immunosuppressed HSCT and SOT recipients (89, 90). In the context of pregnancy, congenital HCMV transmission can occur even in the context of preconception immunity. Indeed, the prevalence of cCMV transmission is highest in high-seroprevalence populations, and such infections can lead to disabilities (91). In pregnant women, the relative contributions of reinfection with a new strain of HCMV (92) versus reactivation of a latent infection (93, 94) indicate that the risks of cCMV transmission have not been fully elucidated.

Subunit, DNA, mRNA, and viral-vectored vaccines (discussed below) have mainly focused on envelope glycoprotein complexes that are targets for neutralizing antibodies (44, 95). These include glycoprotein B (gB), the “fusion glycoprotein” that mediates viral entry into cells by fusing the virion envelope with the cell membrane, and two additional complexes, the trimeric complex (TC), which comprises glycoproteins H, L, and O (gH, gL, and gO), and the pentameric complex (PC), which comprises gH/gL complexed with UL128, UL130, and UL131A. The TC and PC interact with cell surface receptors and then communicate signals to gB to initiate membrane fusion (96). The relative importance of these complexes in viral tropism and cell entry is unresolved, but both have become cornerstones of subunit vaccine design. In vitro evidence suggests that gB is required for HCMV infection of all cell types, and neutralizing antibodies against gB are presumed to contribute to prevention of infection of most if not all cell types in vivo. In contrast, the PC is dispensable for the infection of fibroblasts but required for entry into epithelial, endothelial, and myeloid lineage cells (97–103). Thus, PC-specific antibodies may be advantageous owing to their extraordinary potency (up to 1,000-fold higher than antibodies targeting gB or TC), but this neutralizing activity is limited to epithelial, endothelial, and myeloid cells, with no activity preventing entry into fibroblasts (104–106). Yet, a recent report indicated that the PC is not required for placental CMV transmission in a nonhuman primate cCMV model (107). Subunit vaccines have focused largely on gB, alone or in combination with the TC and/or PC (108–111). However, TC is not required for HCMV entry into mucosal epithelial cells, and therefore, TC-specific antibodies may block HCMV at mucosal surfaces.

T cell responses are essential for protection against HCMV-associated disease, as observed in people with AIDS and organ transplant recipients, yet there is less clarity around their role in protection against virus acquisition. Most HCMV-specific CD8⁺ T cells are terminally differentiated and exhibit immediate effector function with a short life span; mucosal tissue, which represents a site of HCMV reactivation, is primarily populated by tissue resident–memory T cells, which do not recirculate (112). The pp65 (ppUL83) tegument protein is the immunodominant CD8⁺ antigen (113). CD8⁺ T cell responses to HCMV often also include IE-1 as well as structural, early/late antigens, and virus-encoded immunomodulatory proteins such as pp28, pp50, gH, gB, US2, US3, US6, and UL18 (114). In total, more than 151 HCMV ORFs were immunogenic for CD4⁺ and/or CD8⁺ T cell responses (115). CD4⁺ T cell responses have also been identified as critical for protection against disease in SOT recipients as well as against congenital infection in humans and in animal models (116, 117).

With respect to the specific role of T cells for cCMV infection, relatively little is known about their role in protection against maternal-fetal CMV transmission (118–120). Recently, an ex vivo model of HCMV infection utilized samples of decidua collected from women with and without preconception immunity to CMV (121). Explanted decidua from women with preconception immunity to HCMV exhibited intrinsic resistance to HCMV and rapidly mounted CD8⁺ and CD4⁺ T cell responses upon HCMV reinfection. The role of CD8⁺ T cells in protecting the maternal-fetal interface from nonprimary HCMV infections is unclear, as HCMV-specific decidual CD8⁺ T cells express a distinct profile of cytolytic molecules compared with that of circulating T cells (122). Other studies have demonstrated lower cytokine and CD4⁺ T cell responses in maternal-fetal dyads where cCMV transmission occurs (123–125). A GPCMV T cell vaccine targeting GP83 (the GPCMV homolog of HCMV ppUL83) was found to be partially protective against cCMV transmission (126). Thus, vaccine-induced T cell responses require further evaluation as a protective component of preconception immunization.

NK cell functions are also increasingly recognized as important in HCMV immunity, and infection leads to memory NK cell populations (127, 128) as well as induction of NK-like T cells (129, 130), but their role in vaccine-elicited protection remains undefined. The importance of NK responses is suggested by recent studies that suggest that protection against primary maternal HCMV infection is in part mediated by so-called “nonneutralizing” or “Fc-mediated” immune mechanisms, such as antibody-dependent cellular phagocytosis (ADCP) or antibody-dependent cellular cytotoxicity (ADCC) (131–134). Both mechanisms involve antibodies that bind to viral proteins on the surface of infected cells. Engagement of the exposed antibody Fc domains with Fc receptors on effector cells then facilitates either ADCP (if the effector cell is phagocytic) or ADCC (if the effector cell is an NK cell), in both cases resulting in destruction of the infected cell. HCMV proteins UL16 and UL141 are targeted by ADCC (135). ADCC in HCMV tends to favor late gene products (136), an important issue for the first-generation V160 replication-defective vaccine, where the late viral antigens may be suboptimally expressed (137). A third Fc-mediated mechanism, that of complement-dependent cytotoxicity, has been poorly studied in the context of cCMV. Complement enhances the neutralizing potency of HCMV-seropositive human sera by up to 4-fold and for some gB-based vaccines by up to 100-fold (138). Given that several gB monoclonals neutralize only in the presence of complement (139), such vaccines may exhibit a bias toward complement-dependent epitopes.

In addition to preventing primary infection, it is also of interest to consider how an HCMV vaccine might target latent infection, toward the goal of preventing reactivation. For other Herpesviridae (including Varicella-zoster virus [VZV] and herpes simplex virus [HSV]), immunization strategies specifically targeting reactivation from latency are described (140). Prevention of reactivation from latency is of course the hallmark of vaccination against herpes zoster (shingles). The adjuvanted VZV gE subunit vaccine (HZ/su) confers higher protection against herpes zoster than the live attenuated vaccine (140), likely attributable to an enhanced memory T cell response (141). For HSV, similar strategies that enhance tissue resident–memory T cell responses appear valuable in preventing reactivation from latency infection in animal models (142, 143) but have not yet been assessed in human clinical trials. A similarly successful HCMV vaccine capable of preventing reactivation from latency could be useful at limiting reinfections in high seroprevalence populations. The targets of such an approach are only speculative at this time, but the characterization of several HCMV-encoded ORFs, for example, UL133-138, that play key roles in both establishment of and reactivation from latency (144) could, in principle, become the basis for subunit vaccine design. Notably, a replication-impaired, disabled, infectious single-cycle (DISC) virus HCMV vaccine currently in clinical trials, V160 (discussed later in this Review), lacks these ORFs (145). Studies of HCMV latency, in contrast to VZV and HSV, demonstrate that a wide range of viral late gene transcripts are actively expressed, albeit to lower levels than during primary infection (146). Future studies focused on enhancing the broadest and most sustained T cell response to the repertoire of HCMV antigens expressed throughout the viral life cycle could be of value, as well as the investigation of strategies that enhance innate immunity (147), in generating a vaccine capable of reducing reactivation of latent infection.

As natural immunity is not always protective against HCMV reinfection or congenital transmission, the goal of a successful HCMV vaccine will be to elicit immunity that improves on that elicited by natural infection. Current vaccine trials will evaluate the possibility of protection against a range of HCMV strains. Though there is evidence for antigenic variation, it is not certain whether HCMV vaccines with diverse antigens from multiple strains will be required. For example, immunogenicity data from a multistrain gB vaccine demonstrated limited effect on immunity (148). Another possible result of these vaccine trials will be further definition of the immunologic correlates of protection against placental transmission or disease (149). In particular, the role of mucosal immunity in preventing acquisition of HCMV requires more studies. However, it is our view that current knowledge gaps in vaccine design should not temper the urgency of achieving vaccine licensure to address the unmet need for protecting newborns against congenital HCMV transmission. Indeed, in view of the huge scope of the problem, the licensure of even a moderately effective vaccine would be a major public health success.

Generally speaking, HCMV vaccines that have advanced to clinical trial testing can be categorized as subunit vaccines (expressing gene product[s] of importance in protective immunity), using an appropriate source of immunogen (protein, DNA, or RNA) expressed de novo or in the context of an expression vector, or whole-virus vaccines (live, attenuated viruses or DISC viruses). In terms of the immunogen(s) of choice, most subunit vaccine candidates have focused on recombinant gB, the major viral fusogen (150–152) encoded by the UL55 ORF, and the ppUL83, which, as noted above, is the dominant T cell immunogen in the context of infection (113). Emphasis has also been placed on the IE1 and IE2 (encoded by UL123 and UL122, respectively) proteins (153).

Various expression platforms expressing combinations of these immunogens have been studied in humans. A DNA vaccine developed by Astellas, ASP0113, contained two plasmids encoding gB and ppUL83. However, this vaccine had no effect on HCMV disease in a phase II study in setting of SOT (154) or in a phase III study in HSCT (155). This vaccine is not being further developed. Another vaccine candidate, HB-101, is based on expression of gB and ppUL83 using a lymphocytic choriomeningitis virus platform. In a placebo-controlled phase I study, 54 participants that received vaccine demonstrated pp65-specific CD8⁺ T cell responses and neutralizing antibody responses; however, the manufacturer has suspended the product development plan for this vaccine (156). A two-component alphavirus replicon particle vaccine, expressing HCMV gB or a pp65/IE1 fusion protein, was evaluated in a randomized, double-blind phase I clinical trial in HCMV-seronegative individuals (157). Antibody and T cell responses were noted, but the vaccine was not further developed.

With respect to whole-virus vaccines, HCMV strains were engineered in a fashion that was predicted to increase the immunogenicity of the Towne strain by generating genomic reassortments of Towne sequences mixed with a minimally passaged clinical isolate of HCMV, the “Toledo” strain. Four recombinants were tested in phase I studies of small numbers of participants, and one turned out to be suitably immunogenic (158). These so-called “Towne-Toledo chimeras” did not undergo any further testing; one potential deficiency in the platform is that none of the chimeras encode a functional PC (159). None of these chimeric vaccines demonstrated any evidence of “boosting” anti-HCMV immune responses in a phase I study in HCMV-seropositive recipients (160).

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.

Table 1

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.

An important limitation hindering HCMV vaccine development is the gap in our understanding of what components of the immune response would protect against mucosal virus acquisition versus systemic HCMV disease and transfer to the fetus. Immune correlate analyses of the partially protective gB subunit vaccine trials revealed that plasma IgG recognition of gB expressed on the surface of a cell, but not recognition of the soluble gB protein, predicted protection against HCMV acquisition (131). Thus, it is likely that native conformation of gB, as well as other glycoproteins, is critical to elicitation of protective immune responses. While the partially protective DISC V160 vaccine presented membrane-associated glycoprotein antigens, including gB, the magnitude of the immune responses elicited by this alum-adjuvanted vaccine may have limited its efficacy. Vaccines that combine glycoprotein antigens beyond gB, such as the PC that is critical to viral entry into endothelial and epithelial cells, have been assessed in animal models (171, 172) and are currently the basis of the Moderna mRNA-1647 vaccine that is in phase III trials (164, 173). While the high levels of neutralizing antibodies generated by the inclusion of the PC did not generate highly protective responses against mucosal virus acquisition (174) and were not required for prevention of placental infection in nonhuman primate models (107), it is possible that this approach will show more benefit when studied in humans, which may involve lower levels of virus in the natural setting, as opposed to the challenge doses and routes of inoculation used in animal modeling.

The recent success of structurally engineered viral fusion proteins in the development of respiratory syncytial virus and SARS-CoV-2 vaccines reveals the importance of applying structure-based design to HCMV gB and its entry complex partners. Immunization with a fully trimeric (175) or “prefusion” gB conformation (151) has the potential to enhance entry-blocking activity of vaccine-elicited antibodies, though current immunogenicity results in mice have only shown that prefusion gB vaccines elicited neutralizing antibodies equivalent to those conferred by postfusion gB vaccines (176). Moreover, although the field has focused on neutralizing functions, nonneutralizing effector antibody functions such as ADCC and ADCP may be more important than virus-neutralizing antibody responses in mediating protection (177). As there is evidence that T cell responses are likely also essential for both prevention of congenital infection and reduction of complications in SOT and HSCT recipients (123, 178), current vaccine approaches also should focus on the elicitation of T cell immunity. As discussed above, HCMV also employs a number of immune evasion mechanisms to escape host immune responses, such as NK receptor ligand intercepting molecules (179), viral cytokines (180), and viral Fc receptors (181, 182), and novel vaccine strategies are needed to counteract the viral immune evasion functions that contribute to reinfections. Thus, there is a potential to include immune evasion antigens in HCMV vaccine design to elicit blocking antibody responses that can enhance the effectiveness of vaccine-elicited anti-HCMV immunity over that of natural immunity.

The key questions for a vaccine to prevent congenital infection are as follows: (a) how can next-generation HCMV vaccine candidates improve on the nearly 50% efficacy against acquisition of maternal infection in studies reported to date; and (b) what will be required to demonstrate protection against fetal infection and/or sequelae, even if protection against maternal infection is incomplete? As discussed above, maximizing the neutralizing antibody response, as well as the nonneutralizing responses, such as ADCP, in variety of cell types may be achievable by targeting the combination of gB and PC. Additionally, individual pentamer subunits may elicit cellular immune responses that could augment the protection conferred by antibody responses (173). The importance of antipentamer responses in protection against horizontal and congenital transmission has not been fully demonstrated, but an ongoing phase III trial of the mRNA-1647 vaccine encoding both gB and the PC will provide insight into the success of this combined strategy, as it pertains to horizontal transmission (164).

The target populations for HCMV vaccines intended to prevent cCMV infection need to be defined. The National Academy of Medicine modeled a vaccine for cCMV against a target population of 12-year-old boys and girls (183). Candidates for immunization potentially include seronegative individuals before pregnancy, adolescents, and infants or toddlers (183, 184). Toddlers are a particularly important population to consider, since enrollment in group daycare — where CMV transmission frequently occurs — stands as a major risk factor for their parents to acquire the infection via exposure to infectious secretions and body fluids. Inasmuch as the majority of worldwide congenital HCMV infections occur in the fetuses of seropositive individuals who could undergo vaccination to prevent HCMV reinfection or reactivation, a vaccine that enhances preconception immunity is of key importance. A licensed vaccine against congenital HCMV that is useful both in seronegative and seropositive people would be an enormous advancement for public health.

In addition to causing congenital infection, HCMV is one of the most frequent serious infections of patients receiving SOT or HSCT as a result of the immunosuppression that is necessary in these settings. Although the correlates of protection may be different than those that prevent infection of a developing fetus, conferring pretransplant HCMV immunity to patients undergoing transplantation could provide substantial benefits that enhance transplant outcomes, reduce mortality, and protect against the indirect effects of HCMV. HCMV disease occurs both in seronegative transplant recipients undergoing primary infection and also in seropositive recipients due to reactivation of the latent virus. Early studies of an attenuated HCMV strain given to recipients before transplantation showed significant elimination or reduction of disease in both groups (185, 186). However, concerns about the safety of a live vaccine virus shifted studies of HCMV disease prevention to the use of subunit protein antigens (187) and to those same antigens presented by poxvirus vectors (188, 189). Partial success in reduction of HCMV disease after transplantation was accomplished with both approaches. Yet, a gap in the field has prevented the continued development of partially effective vaccines: how do we define the ultimate goal of a HCMV vaccine? Sterile protection may be difficult, but prevention of dissemination in the body and to the fetus may not be.

The CMV vaccine antigen most studied in the setting of SOT is the surface gB glycoprotein, which by itself has shown efficacy in preventing acquisition of HCMV in both seronegative women and also in seronegative transplant recipients (109, 187, 190). Thus, it should be part of any successful HCMV vaccines used in the setting of SOT. However, a T cell–based vaccine is likely necessary to better protect transplant recipients. A vaccine containing gB protein in combination with several CD8⁺ T cell epitopes (Table 1) has demonstrated good B and T cell responses in animals (191). Inclusion of ppUL83 may be desirable for immunization of both HCMV-seronegative and -seropositive patients (192).

As noted above, mRNA technology has recently been applied to the development of HCMV vaccines. The gB protein presented by mRNA induced stronger ADCC and a greater breadth of gB-specific T cell responses than the adjuvanted protein (164, 193). Thus, we now have multiple ways of presenting HCMV antigens to the immune system, which allows induction or enhancement of antibody and cellular immune responses in both seronegative and seropositive individuals (194). Ongoing and completed trials in the SOT and HSCT setting have focused on therapeutic vaccination to prevent or reduce viremia. Evaluation of these vaccine candidates against HCMV-related disease in transplant recipients is an important next step in the development pipeline, drawing on comparisons to studies performed in parallel with vaccines primarily focused on prevention of cCMV (Table 1).

In summary, the 2023 NIAID meeting proceeding revealed that the recent entry into clinical trials of multiple HCMV vaccines gives hope that intrauterine infection and transplant complications can be substantially reduced in the near future (195). It was noted that investigations of immune correlates in human populations and mechanistic studies of HCMV disease in preclinical models should continue and should be related to the responses elicited by distinct HCMV vaccine platforms. Further emphasis was placed on defining virologic and disease outcome measures for ongoing vaccine assessments. A consensus conclusion of this meeting of HCMV vaccine experts was that if current vaccine candidates in late-stage trials result in the safe protection of the majority of vaccinees against HCMV infection and/or disease, they should be reviewed for licensure. Even partial success of these candidate vaccines against HCMV is likely to have an enormous effect in reducing CMV-associated congenital disease in children as well as disease in SOT and HSCT recipients globally, and acceleration of promising candidates through the regulatory pathway should be a high priority.

This work was supported by grants: NIH R01 HD099866 (to MRS), 1R01AI173333 (to SP), and 2P01AI129859 (to SP).

Address correspondence to: Sallie R. Permar, 525 East 68th Street, Box 225, New York, New York 10065, USA. Email: sallie.permar@med.cornell.edu.

Conflict of interest: SRP has served as a consultant to Moderna, Merck, Dynavax, Pfizer, Hookipa, and GSK on vaccine development and has led sponsored programs with Merck and Moderna on CMV vaccines. MRS has served as a consultant to Moderna, Merck, and GSK. SAP has served as a consultant to GSK, VBI Vaccines, Merck, and Moderna.

Copyright: © 2025, Permar et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2025;135(1):e182317. https://doi.org/10.1172/JCI182317.

1. Picone O, et al. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn. 2013;33(8):751–758.
   View this article via: CrossRef PubMed Google Scholar
2. Enders G, et al. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J Clin Virol. 2011;52(3):244–246.
   View this article via: CrossRef PubMed Google Scholar
3. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–276.
   View this article via: CrossRef PubMed Google Scholar
4. Fowler KB, et al. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA. 2003;289(8):1008–1011.
   View this article via: CrossRef PubMed Google Scholar
5. Leruez-Ville M, et al. Risk factors for congenital cytomegalovirus infection following primary and nonprimary maternal infection: a prospective neonatal screening study using polymerase chain reaction in saliva. Clin Infect Dis. 2017;65(3):398–404.
   View this article via: CrossRef PubMed Google Scholar
6. Simonazzi G, et al. Perinatal outcomes of non-primary maternal cytomegalovirus infection: a 15-year experience. Fetal Diagn Ther. 2018;43(2):138–142.
   View this article via: CrossRef PubMed Google Scholar
7. Ross SA, et al. Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr. 2006;148(3):332–336.
   View this article via: CrossRef PubMed Google Scholar
8. Khawaja F, et al. Cytomegalovirus infection in transplant recipients: newly approved additions to our armamentarium. Clin Microbiol Infect. 2023;29(1):44–50.
   View this article via: CrossRef PubMed Google Scholar
9. Royston L, et al. Refractory/resistant cytomegalovirus infection in transplant recipients: an update. Viruses. 2024;16(7):1085.
   View this article via: CrossRef PubMed Google Scholar
10. Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. I. N Engl J Med. 1971;285(4):203–214.
    View this article via: CrossRef PubMed Google Scholar
11. Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. II. N Engl J Med. 1971;285(5):267–274.
    View this article via: CrossRef PubMed Google Scholar
12. Zuhair M, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol. 2019;29(3):e2034.
    View this article via: CrossRef PubMed Google Scholar
13. Fowler K, et al. A systematic literature review of the global seroprevalence of cytomegalovirus: possible implications for treatment, screening, and vaccine development. BMC Public Health. 2022;22(1):1659.
    View this article via: CrossRef PubMed Google Scholar
14. Nolan N, et al. Primary cytomegalovirus infection in immunocompetent adults in the United States - A case series. IDCases. 2017;10:123–126.
    View this article via: CrossRef PubMed Google Scholar
15. Horwitz CA, et al. Clinical and laboratory evaluation of cytomegalovirus-induced mononucleosis in previously healthy individuals. Report of 82 cases. Medicine (Baltimore). 1986;65(2):124–134.
    View this article via: CrossRef PubMed Google Scholar
16. Schleiss MR. Acquisition of human cytomegalovirus infection in infants via breast milk: natural immunization or cause for concern? Rev Med Virol. 2006;16(2):73–82.
    View this article via: CrossRef PubMed Google Scholar
17. Ford-Jones EL, et al. Cytomegalovirus infections in Toronto child-care centers: a prospective study of viral excretion in children and seroconversion among day-care providers. Pediatr Infect Dis J. 1996;15(6):507–514.
    View this article via: CrossRef PubMed Google Scholar
18. Joseph SA, et al. Cytomegalovirus as an occupational risk in daycare educators. Paediatr Child Health. 2006;11(7):401–407.
    View this article via: CrossRef PubMed Google Scholar
19. Bale JF Jr. Cytomegalovirus transmission in child care homes. Arch Pediatr Adolesc Med. 1999;153(1):75–79.
    View this article via: CrossRef PubMed Google Scholar
20. Adler SP. Cytomegalovirus and child day care: risk factors for maternal infection. Pediatr Infect Dis J. 1991;10(8):590–594.
    View this article via: CrossRef PubMed Google Scholar
21. Pass RF, et al. Increased rate of cytomegalovirus infection among day care center workers. Pediatr Infect Dis J. 1990;9(7):465–470.
    View this article via: CrossRef PubMed Google Scholar
22. Stadler LP, et al. Seroprevalence of cytomegalovirus (CMV) and risk factors for infection in adolescent males. Clin Infect Dis. 2010;51(10):e76–e81.
    View this article via: CrossRef PubMed Google Scholar
23. Stadler LP, et al. Seroprevalence and risk factors for cytomegalovirus infections in adolescent females. J Pediatric Infect Dis Soc. 2013;2(1):7–14.
    View this article via: CrossRef PubMed Google Scholar
24. Sohn YM, et al. Cytomegalovirus infection in sexually active adolescents. J Infect Dis. 1991;163(3):460–463.
    View this article via: CrossRef PubMed Google Scholar
25. Osterholm EA, Schleiss MR. Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis, prevention, and clinical consequences? Rev Med Virol. 2020;30(6):1–11.
    View this article via: CrossRef PubMed Google Scholar
26. Weimer KED, et al. Association of adverse hearing, growth, and discharge age outcomes with postnatal cytomegalovirus infection in infants with very low birth weight. JAMA Pediatr. 2020;174(2):133.
    View this article via: CrossRef PubMed Google Scholar
27. Poole E, Sinclair J. Sleepless latency of human cytomegalovirus. Med Microbiol Immunol. 2015;204(3):421–429.
    View this article via: CrossRef PubMed Google Scholar
28. Forte E, et al. Cytomegalovirus latency and reactivation: an intricate interplay with the host immune response. Front Cell Infect Microbiol. 2020;10:130.
    View this article via: CrossRef PubMed Google Scholar
29. Poole E, Sinclair J. Understanding HCMV latency using unbiased proteomic analyses. Pathogens. 2020;9(7):590.
    View this article via: CrossRef PubMed Google Scholar
30. Allaw F, et al. Management of cytomegalovirus infection in allogeneic hematopoietic stem cell transplants. Int J Antimicrob Agents. 2023;62(2):106860.
    View this article via: CrossRef PubMed Google Scholar
31. Zakhour J, et al. The ten most common questions on cytomegalovirus infection in hematopoietic stem cell transplant patients. Clin Hematol Int. 2023;5(1):21–28.
    View this article via: CrossRef PubMed Google Scholar
32. Kotton CN, Kamar N. New insights on CMV management in solid organ transplant patients: prevention, treatment, and management of resistant/refractory disease. Infect Dis Ther. 2023;12(2):333–342.
    View this article via: CrossRef PubMed Google Scholar
33. Heald-Sargent TA, et al. New insights into the molecular mechanisms and immune control of cytomegalovirus reactivation. Transplantation. 2020;104(5):e118–e124.
    View this article via: CrossRef PubMed Google Scholar
34. Dollard SC, et al. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–363.
    View this article via: CrossRef PubMed Google Scholar
35. Korndewal MJ, et al. Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study. Dev Med Child Neurol. 2017;59(12):1261–1268.
    View this article via: CrossRef PubMed Google Scholar
36. Salome S, et al. Congenital cytomegalovirus infection: the state of the art and future perspectives. Front Pediatr. 2023;11:1276912.
    View this article via: CrossRef PubMed Google Scholar
37. Meyers J, et al. The economic burden of congenital cytomegalovirus disease in the first year of life: a retrospective analysis of health insurance claims data in the United States. Clin Ther. 2019;41(6):1040–1056.e3.
    View this article via: CrossRef PubMed Google Scholar
38. Inagaki K, et al. Risk factors, geographic distribution, and healthcare burden of symptomatic congenital cytomegalovirus infection in the United States: analysis of a nationally representative database, 2000-2012. J Pediatr. 2018;199:118–123.e1.
    View this article via: CrossRef PubMed Google Scholar
39. Morton CC, Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med. 2006;354(20):2151–2164.
    View this article via: CrossRef PubMed Google Scholar
40. Geris JM, et al. Evaluation of the association between congenital cytomegalovirus infection and pediatric acute lymphoblastic leukemia. JAMA Netw Open. 2023;6(1):e2250219.
    View this article via: CrossRef PubMed Google Scholar
41. Toor RK, et al. Does congenital cytomegalovirus infection contribute to the development of acute lymphoblastic leukemia in children? Curr Opin Virol. 2023;60:101325.
    View this article via: CrossRef PubMed Google Scholar
42. Francis SS, et al. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood. 2017;129(12):1680–1684.
    View this article via: CrossRef PubMed Google Scholar
43. Gallant RE, et al. Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children. Int J Cancer. 2023;152(5):845–853.
    View this article via: CrossRef PubMed Google Scholar
44. Permar SR, et al. Advancing our understanding of protective maternal immunity as a guide for development of vaccines to reduce congenital cytomegalovirus infections. J Virol. 2018;92(7):e00030-18.
    View this article via: CrossRef PubMed Google Scholar
45. Britt WJ. Congenital human cytomegalovirus infection and the enigma of maternal immunity. J Virol. 2017;91(15):e02392-16.
    View this article via: CrossRef PubMed Google Scholar
46. Lantos PM, et al. The excess burden of cytomegalovirus in African American communities: a geospatial analysis. Open Forum Infect Dis. 2015;2(4):ofv180.
    View this article via: CrossRef PubMed Google Scholar
47. Lantos PM, et al. Geographic disparities in cytomegalovirus infection during pregnancy. J Pediatric Infect Dis Soc. 2017;6(3):e55.
    View this article via: CrossRef PubMed Google Scholar
48. Fowler KB, et al. Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990. J Infect Dis. 1993;168(3):552–556.
    View this article via: CrossRef PubMed Google Scholar
49. de Vries JJ, et al. The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model. Rev Med Virol. 2013;23(4):241–249.
    View this article via: CrossRef PubMed Google Scholar
50. Krause PR, et al. Priorities for CMV vaccine development. Vaccine. 2013;32(1):4–10.
    View this article via: CrossRef PubMed Google Scholar
51. Haidar G, et al. Cytomegalovirus infection in solid organ and hematopoietic cell transplantation: state of the evidence. J Infect Dis. 2020;221(suppl 1):S23–S31.
    View this article via: CrossRef PubMed Google Scholar
52. Kim WR, et al. The economic impact of cytomegalovirus infection after liver transplantation. Transplantation. 2000;69(3):357–361.
    View this article via: CrossRef PubMed Google Scholar
53. Shahar-Nissan K, et al. Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10253):779–785.
    View this article via: CrossRef PubMed Google Scholar
54. Bourgon N, et al. In utero treatment of congenital cytomegalovirus infection with valganciclovir: an observational study on safety and effectiveness. J Antimicrob Chemother. 2024;79(10):2500–2508.
    View this article via: CrossRef PubMed Google Scholar
55. Kotton CN, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–931.
    View this article via: CrossRef PubMed Google Scholar
56. Ljungman P, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(8):260–272.
57. Kotton CN, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–931.
    View this article via: CrossRef PubMed Google Scholar
58. Deray KGV, et al. Current and emerging antiviral agents in the prevention and treatment of cytomegalovirus in pediatric transplant recipients. J Pediatric Infect Dis Soc. 2024;13(suppl_1):S14–S21.
59. Yu C, et al. Human cytomegalovirus in cancer: the mechanism of HCMV-induced carcinogenesis and its therapeutic potential. Front Cell Infect Microbiol. 2023;13:1202138.
    View this article via: CrossRef PubMed Google Scholar
60. Geisler J, et al. A review of the potential role of human cytomegalovirus (HCMV) infections in breast cancer carcinogenesis and abnormal immunity. Cancers (Basel). 2019;11(12):1842.
    View this article via: CrossRef PubMed Google Scholar
61. Chen S, et al. Associations of cytomegalovirus infection with all-cause and cardiovascular mortality in multiple observational cohort studies of older adults. J Infect Dis. 2021;223(2):238–246.
    View this article via: CrossRef PubMed Google Scholar
62. Simanek AM, et al. Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One. 2011;6(2):e16103.
    View this article via: CrossRef PubMed Google Scholar
63. Vasilieva E, et al. Novel strategies to combat CMV-related cardiovascular disease. Pathog Immun. 2020;5(1):240.
    View this article via: CrossRef PubMed Google Scholar
64. Kua KP, et al. Association between cytomegalovirus infection and tuberculosis disease: a systematic review and meta-analysis of epidemiological studies. J Infect Dis. 2023;227(4):471–482.
    View this article via: CrossRef PubMed Google Scholar
65. Muller J, et al. Cytomegalovirus infection is a risk factor for tuberculosis disease in infants. JCI Insight. 2019;4(23):e130090.
    View this article via: JCI Insight CrossRef PubMed Google Scholar
66. Martinez L, et al. Cytomegalovirus acquisition in infancy and the risk of tuberculosis disease in childhood: a longitudinal birth cohort study in Cape Town, South Africa. Lancet Glob Health. 2021;9(12):e1740–e1749.
    View this article via: CrossRef PubMed Google Scholar
67. Skipper C, et al. Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in Sub-Saharan Africa. Clin Infect Dis. 2020;71(3):525.
    View this article via: CrossRef PubMed Google Scholar
68. Muller L, Di Benedetto S. Immunosenescence and cytomegalovirus: exploring their connection in the context of aging, health, and disease. Int J Mol Sci. 2024;25(2):753.
    View this article via: CrossRef PubMed Google Scholar
69. van den Berg SPH, et al. Effect of latent cytomegalovirus infection on the antibody response to influenza vaccination: a systematic review and meta-analysis. Med Microbiol Immunol. 2019;208(3-4):305–321.
    View this article via: CrossRef PubMed Google Scholar
70. Freeman ML, et al. Association of cytomegalovirus serostatus with severe acute respiratory syndrome coronavirus 2 vaccine responsiveness in nursing home residents and healthcare workers. Open Forum Infect Dis. 2023;10(2):ofad063.
    View this article via: CrossRef PubMed Google Scholar
71. Imlay H, Limaye AP. Current understanding of cytomegalovirus reactivation in critical illness. J Infect Dis. 2020;221(suppl 1):S94–S102.
    View this article via: CrossRef PubMed Google Scholar
72. Limaye AP, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–422.
    View this article via: CrossRef PubMed Google Scholar
73. Schleiss MR. Persistent and recurring viral infections: the human herpesviruses. Curr Probl Pediatr Adolesc Health Care. 2009;39(1):7–23.
    View this article via: PubMed Google Scholar
74. Pesch MH, Schleiss MR. Emerging concepts in congenital cytomegalovirus. Pediatrics. 2022;150(2):e2021055896.
    View this article via: CrossRef PubMed Google Scholar
75. Renzette N, et al. Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection. PLoS Genet. 2013;9(9):e1003735.
    View this article via: CrossRef PubMed Google Scholar
76. Renzette N, et al. Limits and patterns of cytomegalovirus genomic diversity in humans. Proc Natl Acad Sci U S A. 2015;112(30):E4120–E4128.
    View this article via: CrossRef PubMed Google Scholar
77. Charles OJ, et al. Genomic and geographical structure of human cytomegalovirus. Proc Natl Acad Sci U S A. 2023;120(30):e2221797120.
    View this article via: CrossRef PubMed Google Scholar
78. Halenius A, et al. Classical and non-classical MHC I molecule manipulation by human cytomegalovirus: so many targets—but how many arrows in the quiver? Cell Mol Immunol. 2015;12(2):139–153.
    View this article via: CrossRef PubMed Google Scholar
79. Jackson SE, et al. Human cytomegalovirus (HCMV)-specific CD4⁺ T cells are polyfunctional and can respond to HCMV-infected dendritic cells in vitro. J Virol. 2017;91(6):e02128-16.
    View this article via: CrossRef PubMed Google Scholar
80. Charpak-Amikam Y, et al. Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20. Sci Rep. 2017;7(1):8661.
    View this article via: CrossRef PubMed Google Scholar
81. Patel M, et al. HCMV-encoded NK modulators: lessons from in vitro and in vivo genetic variation. Front Immunol. 2018;9:2214.
    View this article via: CrossRef PubMed Google Scholar
82. Nachmani D, et al. The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination. Nat Immunol. 2010;11(9):806–813.
    View this article via: CrossRef PubMed Google Scholar
83. Kotenko SV, et al. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci U S A. 2000;97(4):1695–1700.
    View this article via: CrossRef PubMed Google Scholar
84. Chang WL, et al. Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. J Virol. 2004;78(16):8720–8731.
    View this article via: CrossRef PubMed Google Scholar
85. Poole E, et al. Human cytomegalovirus interleukin 10 homologs: facing the immune system. Front Cell Infect Microbiol. 2020;10:245.
    View this article via: CrossRef PubMed Google Scholar
86. Beisser PS, et al. Chemokines and chemokine receptors encoded by cytomegaloviruses. Curr Top Microbiol Immunol. 2008;325:221–242.
    View this article via: PubMed Google Scholar
87. Krishna BA, et al. US28: HCMV’s Swiss army knife. Viruses. 2018;10(8):445.
    View this article via: CrossRef PubMed Google Scholar
88. Corrales-Aguilar E, et al. CMV-encoded Fcγ receptors: modulators at the interface of innate and adaptive immunity. Semin Immunopathol. 2014;36(6):627–640.
    View this article via: CrossRef PubMed Google Scholar
89. Razonable RR. Cytomegalovirus in solid organ transplant recipients: clinical updates, challenges and future directions. Curr Pharm Des. 2020;26(28):3497.
    View this article via: CrossRef PubMed Google Scholar
90. Ljungman P, et al. Consensus definitions of cytomegalovirus (CMV) infection and disease in transplant patients including resistant and refractory CMV for use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum. Clin Infect Dis. 2024;79(3):787–794.
    View this article via: CrossRef PubMed Google Scholar
91. Mussi-Pinhata MM, et al. Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population. Clin Infect Dis. 2009;49(4):522–528.
    View this article via: CrossRef PubMed Google Scholar
92. Boppana SB, et al. Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med. 2001;344(18):1366–1371.
    View this article via: CrossRef PubMed Google Scholar
93. Brosh-Nissimov T, et al. Recurrent congenital cytomegalovirus infection in a sequential pregnancy with severe sequelae, and a possible association with prophylactic valacyclovir treatment: a case report. Int J Infect Dis. 2022;125:93–95.
    View this article via: CrossRef PubMed Google Scholar
94. Nagamori T, et al. Single cytomegalovirus strain associated with fetal loss and then congenital infection of a subsequent child born to the same mother. J Clin Virol. 2010;49(2):134–136.
    View this article via: CrossRef PubMed Google Scholar
95. Schleiss MR, et al. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin Vaccine Immunol. 2017;24(12):e00268-17.
    View this article via: CrossRef PubMed Google Scholar
96. Nguyen CC, Kamil JP. Pathogen at the gates: human cytomegalovirus entry and cell tropism. Viruses. 2018;10(12):704.
    View this article via: CrossRef PubMed Google Scholar
97. Zhou M, et al. Human cytomegalovirus gH/gL/gO promotes the fusion step of entry into all cell types, whereas gH/gL/UL128-131 broadens virus tropism through a distinct mechanism. J Virol. 2015;89(17):8999.
    View this article via: CrossRef PubMed Google Scholar
98. Wang D, Shenk T. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci U S A. 2005;102(50):18153–18158.
    View this article via: CrossRef PubMed Google Scholar
99. Wille PT, et al. A human cytomegalovirus gO-null mutant fails to incorporate gH/gL into the virion envelope and is unable to enter fibroblasts and epithelial and endothelial cells. J Virol. 2010;84(5):2585–2596.
    View this article via: CrossRef PubMed Google Scholar
100. Wille PT, et al. Human cytomegalovirus (HCMV) glycoprotein gB promotes virus entry in trans acting as the viral fusion protein rather than as a receptor-binding protein. mBio. 2013;4(3):e00332–e00313.
     View this article via: CrossRef PubMed Google Scholar
101. Heldwein EE. gH/gL supercomplexes at early stages of herpesvirus entry. Curr Opin Virol. 2016;18:1–8.
     View this article via: CrossRef PubMed Google Scholar
102. Ryckman BJ, et al. Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol. 2006;80(2):710–722.
     View this article via: CrossRef PubMed Google Scholar
103. Gardner TJ, Tortorella D. Virion glycoprotein-mediated immune evasion by human cytomegalovirus: a sticky virus makes a slick getaway. Microbiol Mol Biol Rev. 2016;80(3):663–677.
     View this article via: CrossRef PubMed Google Scholar
104. Macagno A, et al. Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol. 2010;84(2):1005.
     View this article via: CrossRef PubMed Google Scholar
105. Ha S, et al. Neutralization of diverse human cytomegalovirus strains conferred by antibodies targeting viral gH/gL/pUL128-131 pentameric complex. J Virol. 2017;91(7):e02033-16.
     View this article via: CrossRef PubMed Google Scholar
106. Cui X, et al. Impact of antibodies and strain polymorphisms on cytomegalovirus entry and spread in fibroblasts and epithelial cells. J Virol. 2017;91(13):e01650-16.
     View this article via: CrossRef PubMed Google Scholar
107. Wang HY, et al. The pentameric complex is not required for vertical transmission of cytomegalovirus in seronegative pregnant rhesus macaques [preprint]. https://doi.org/10.1101/2023.06.15.545169 Posted on bioRxiv June 16, 2023.
108. Pass RF, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360(12):1191–1199.
     View this article via: CrossRef PubMed Google Scholar
109. Bernstein DI, et al. Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial. Vaccine. 2016;34(3):313–319.
     View this article via: CrossRef PubMed Google Scholar
110. Cui X, et al. Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine. 2008;26(45):5760–5766.
     View this article via: CrossRef PubMed Google Scholar
111. Fierro C, et al. Safety and immunogenicity of a messenger RNA-based cytomegalovirus vaccine in healthy adults: results from a phase 1 randomized Clinical Trial. J Infect Dis. 2024;230(3):e668–e678.
     View this article via: CrossRef PubMed Google Scholar
112. Smith CJ, et al. CMV-specific CD8 T cell differentiation and localization: implications for adoptive therapies. Front Immunol. 2016;7:352.
     View this article via: CrossRef PubMed Google Scholar
113. Wills MR, et al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol. 1996;70(11):7569–7579.
     View this article via: CrossRef PubMed Google Scholar
114. Elkington R, et al. Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol. 2003;77(9):5226–5240.
     View this article via: CrossRef PubMed Google Scholar
115. Sylwester AW, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–685.
     View this article via: CrossRef PubMed Google Scholar
116. Carvalho-Gomes A, et al. Cytomegalovirus specific polyfunctional T-cell responses expressing CD107a predict control of CMV infection after liver transplantation. Cell Immunol. 2022;371:104455.
     View this article via: CrossRef PubMed Google Scholar
117. Snyder LD, et al. Polyfunctional T-cell signatures to predict protection from cytomegalovirus after lung transplantation. Am J Respir Crit Care Med. 2016;193(1):78–85.
     View this article via: CrossRef PubMed Google Scholar
118. Zangger N, Oxenius A. T cell immunity to cytomegalovirus infection. Curr Opin Immunol. 2022;77:102185.
     View this article via: CrossRef PubMed Google Scholar
119. Gibson L, et al. Reduced frequencies of polyfunctional CMV-specific T cell responses in infants with congenital CMV infection. J Clin Immunol. 2015;35(3):289–301.
     View this article via: CrossRef PubMed Google Scholar
120. Materne EC, et al. Cytomegalovirus-specific T cell epitope recognition in congenital cytomegalovirus mother-infant pairs. Front Immunol. 2020;11:568217.
     View this article via: CrossRef Google Scholar
121. Alfi O, et al. Decidual-tissue-resident memory T cells protect against nonprimary human cytomegalovirus infection at the maternal-fetal interface. Cell Rep. 2024;43(2):113698.
     View this article via: CrossRef PubMed Google Scholar
122. van der Zwan A, et al. Mixed signature of activation and dysfunction allows human decidual CD8(+) T cells to provide both tolerance and immunity. Proc Natl Acad Sci U S A. 2018;115(2):385.
     View this article via: CrossRef PubMed Google Scholar
123. Lilleri D, et al. Development of human cytomegalovirus-specific T cell immunity during primary infection of pregnant women and its correlation with virus transmission to the fetus. J Infect Dis. 2007;195(7):1062–1070.
     View this article via: CrossRef PubMed Google Scholar
124. Lilleri D, et al. Human cytomegalovirus-specific memory CD8+ and CD4+ T cell differentiation after primary infection. J Infect Dis. 2008;198(4):536–543.
     View this article via: CrossRef PubMed Google Scholar
125. Revello MG, et al. Lymphoproliferative response in primary human cytomegalovirus (HCMV) infection is delayed in HCMV transmitter mothers. J Infect Dis. 2006;193(2):269–276.
     View this article via: CrossRef PubMed Google Scholar
126. Schleiss MR, et al. Preconceptual administration of an alphavirus replicon UL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome in the guinea pig model of congenital cytomegalovirus infection. J Infect Dis. 2007;195(6):789–798.
     View this article via: CrossRef PubMed Google Scholar
127. Sheppard S, Sun JC. Virus-specific NK cell memory. J Exp Med. 2021;218(4):e20201731.
     View this article via: CrossRef PubMed Google Scholar
128. Vaaben AV, et al. In utero activation of natural killer cells in congenital cytomegalovirus infection. J Infect Dis. 2022;226(4):566–575.
     View this article via: CrossRef PubMed Google Scholar
129. Semmes EC, et al. In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions [preprint]. https://doi.org/10.1101/2023.09.08.23295279 Posted on medRxiv September 11, 2023.
130. Sottile R, et al. Human cytomegalovirus expands a CD8⁺ T cell population with loss of BCL11B expression and gain of NK cell identity. Sci Immunol. 2021;6(63):eabe6968.
     View this article via: CrossRef PubMed Google Scholar
131. Nelson CS, et al. HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc Natl Acad Sci U S A. 2018;115(24):6267–6272.
     View this article via: CrossRef PubMed Google Scholar
132. Jenks JA, et al. The roles of host and viral antibody fc receptors in herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections and immunity. Front Immunol. 2019;10:2110.
     View this article via: CrossRef PubMed Google Scholar
133. Semmes EC, et al. ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission. JCI Insight. 2023;8(13):e167768.
     View this article via: JCI Insight CrossRef PubMed Google Scholar
134. Semmes EC, et al. Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection. J Clin Invest. 2022;132(16):e156827.
     View this article via: JCI CrossRef PubMed Google Scholar
135. Vlahava VM, et al. Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus. J Clin Invest. 2021;131(4):e139296.
     View this article via: JCI CrossRef PubMed Google Scholar
136. d’Angelo P, et al. Evaluation of the in vitro capacity of anti-human cytomegalovirus antibodies to initiate antibody-dependent cell cytotoxicity. Microorganisms. 2024;12(7):1355.
     View this article via: CrossRef PubMed Google Scholar
137. Ye X, et al. Transcriptional signature of durable effector T cells elicited by a replication defective HCMV vaccine. NPJ Vaccines. 2024;9(1):70.
     View this article via: CrossRef PubMed Google Scholar
138. McVoy MA, et al. A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells. Vaccine. 2015;33(51):7328–7336.
     View this article via: CrossRef PubMed Google Scholar
139. Li F, et al. Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination. NPJ Vaccines. 2017;2:36.
     View this article via: CrossRef PubMed Google Scholar
140. Levin MJ, et al. Th1 memory differentiates recombinant from live herpes zoster vaccines. J Clin Invest. 2018;128(10):4429–4440.
     View this article via: JCI CrossRef PubMed Google Scholar
141. Gershon AA. Tale of two vaccines: differences in response to herpes zoster vaccines. J Clin Invest. 2018;128(10):4245–4247.
     View this article via: JCI CrossRef PubMed Google Scholar
142. Bernstein DI, et al. Successful application of prime and pull strategy for a therapeutic HSV vaccine. NPJ Vaccines. 2019;4:33.
     View this article via: CrossRef PubMed Google Scholar
143. Chentoufi AA, et al. Combinatorial herpes simplex vaccine strategies: from bedside to bench and back. Front Immunol. 2022;13:849515.
     View this article via: CrossRef PubMed Google Scholar
144. Mlera L, et al. The role of the human cytomegalovirus UL133-UL138 gene locus in latency and reactivation. Viruses. 2020;12(7):714.
     View this article via: CrossRef PubMed Google Scholar
145. Wang D, et al. A replication-defective human cytomegalovirus vaccine for prevention of congenital infection. Sci Transl Med. 2016;8(362):362ra145.
     View this article via: CrossRef PubMed Google Scholar
146. Shnayder M, et al. Defining the transcriptional landscape during cytomegalovirus latency with single-cell RNA sequencing. mBio. 2018;9(2):e00013-18.
     View this article via: CrossRef PubMed Google Scholar
147. Shnayder M, et al. Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state. Elife. 2020;9:e52168.
     View this article via: CrossRef PubMed Google Scholar
148. Wang HY, et al. Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody breadth. NPJ Vaccines. 2024;9(1):38.
     View this article via: CrossRef PubMed Google Scholar
149. Marchant A, et al. Establishing correlates of maternal-fetal cytomegalovirus transmission-one step closer through predictive modeling. [published online June 12, 2024]. J Infect Dis. https://doi.org/10.1093/infdis/jiae281.
     View this article via: PubMed Google Scholar
150. Britt WJ, et al. Cell surface expression of human cytomegalovirus (HCMV) gp55-116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response. J Virol. 1990;64(3):1079–1085.
     View this article via: CrossRef PubMed Google Scholar
151. Liu Y, et al. Prefusion structure of human cytomegalovirus glycoprotein B and structural basis for membrane fusion. Sci Adv. 2021;7(10):eabf3178.
     View this article via: CrossRef PubMed Google Scholar
152. Reuter N, et al. Cell fusion induced by a fusion-active form of human cytomegalovirus glycoprotein B (gB) is inhibited by antibodies directed at antigenic domain 5 in the ectodomain of gB. J Virol. 2020;94(18):e01276-20.
     View this article via: CrossRef PubMed Google Scholar
153. Braendstrup P, et al. Identification and HLA-tetramer-validation of human CD4+ and CD8+ T cell responses against HCMV proteins IE1 and IE2. PLoS One. 2014;9(4):e94892.
     View this article via: CrossRef PubMed Google Scholar
154. Vincenti F, et al. A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Am J Transplant. 2018;18(12):2945–2954.
     View this article via: CrossRef PubMed Google Scholar
155. Ljungman P, et al. A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients. EClinicalMedicine. 2021;33:100787.
     View this article via: CrossRef PubMed Google Scholar
156. Schwendinger M, et al. A randomized dose-escalating phase I trial of a replication-deficient lymphocytic choriomeningitis virus vector-based vaccine against human cytomegalovirus. J Infect Dis. 2022;225(8):1399.
     View this article via: CrossRef PubMed Google Scholar
157. Bernstein DI, et al. Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine. 2009;28(2):484–493.
     View this article via: CrossRef PubMed Google Scholar
158. Adler SP, et al. A Phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimera vaccines in cytomegalovirus-seronegative men. J Infect Dis. 2016;214(9):1341.
     View this article via: CrossRef PubMed Google Scholar
159. Suarez NM, et al. Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo. Virus Genes. 2017;53(4):650–655.
     View this article via: CrossRef PubMed Google Scholar
160. Heineman TC, et al. A phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimeric vaccines. J Infect Dis. 2006;193(10):1350–1360.
     View this article via: CrossRef PubMed Google Scholar
161. Glazer JP, et al. Live cytomegalovirus vaccination of renal transplant candidates. A preliminary trial. Ann Intern Med. 1979;91(5):676–683.
     View this article via: CrossRef PubMed Google Scholar
162. Langley JM, et al. An enveloped virus-like particle alum-adjuvanted cytomegalovirus vaccine is safe and immunogenic: A first-in-humans Canadian Immunization Research Network (CIRN) study. Vaccine. 2024;42(3):713.
     View this article via: CrossRef PubMed Google Scholar
163. Wu K, et al. Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults. J Virol. 2024;98(4):e0160323.
     View this article via: CrossRef PubMed Google Scholar
164. Hu X, et al. Human cytomegalovirus mRNA-1647 vaccine candidate elicits potent and broad neutralization and higher antibody-dependent cellular cytotoxicity responses than the gB/MF59 vaccine. J Infect Dis. 2024;230(2):455–466.
     View this article via: CrossRef PubMed Google Scholar
165. Aldoss I, et al. Poxvirus vectored cytomegalovirus vaccine to prevent cytomegalovirus viremia in transplant recipients: a phase 2, Randomized Clinical Trial. Ann Intern Med. 2020;172(5):306–316.
     View this article via: CrossRef PubMed Google Scholar
166. Yll-Pico M, et al. Highly stable and immunogenic CMV T cell vaccine candidate developed using a synthetic MVA platform. NPJ Vaccines. 2024;9(1):68.
     View this article via: CrossRef PubMed Google Scholar
167. Nakamura R, et al. A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant. Haematologica. 2024;109(6):1994–1999.
     View this article via: PubMed Google Scholar
168. Das R, et al. Safety, efficacy, and immunogenicity of a replication-defective human cytomegalovirus vaccine, V160, in cytomegalovirus-seronegative women: a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Infect Dis. 2023;23(12):1383–1394.
     View this article via: CrossRef PubMed Google Scholar
169. Adler SP, et al. Phase 1 clinical trial of a conditionally replication-defective human cytomegalovirus (CMV) vaccine in CMV-seronegative subjects. J Infect Dis. 2019;220(3):411–419.
     View this article via: CrossRef PubMed Google Scholar
170. Liu Y, et al. A replication-defective human cytomegalovirus vaccine elicits humoral immune responses analogous to those with natural infection. J Virol. 2019;93(23):e00747-19.
     View this article via: CrossRef PubMed Google Scholar
171. Coleman S, et al. A homolog pentameric complex dictates viral epithelial tropism, pathogenicity and congenital infection rate in guinea pig cytomegalovirus. PLoS Pathog. 2016;12(7):e1005755.
     View this article via: CrossRef PubMed Google Scholar
172. Schleiss MR, et al. Inclusion of the guinea pig cytomegalovirus pentameric complex in a live virus vaccine aids efficacy against congenital infection but is not essential for improving maternal andneonatal outcomes. Viruses. 2021;13(12):2370.
     View this article via: CrossRef PubMed Google Scholar
173. John S, et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine. 2018;36(12):1689–1699.
     View this article via: CrossRef PubMed Google Scholar
174. Li J, et al. Horizontal transmission of cytomegalovirus in a rhesus model despite high-level, vaccine-elicited neutralizing antibody and T-cell responses. J Infect Dis. 2022;226(4):585–594.
     View this article via: CrossRef PubMed Google Scholar
175. Cui X, et al. Novel trimeric human cytomegalovirus glycoprotein B elicits a high-titer neutralizing antibody response. Vaccine. 2018;36(37):5580–5590.
     View this article via: CrossRef PubMed Google Scholar
176. Sponholtz MR, et al. Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation. Proc Natl Acad U S A. 2024;121(37):e2404250121.
     View this article via: CrossRef PubMed Google Scholar
177. Semmes EC, et al. ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection [preprint]. https://doi.org/10.1101/2023.03.15.23287332 Posted on medRxiv March 17, 2023;.
178. Bialas KM, et al. Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. Proc Natl Acad Sci U S A. 2015;112(44):13645–13650.
     View this article via: CrossRef PubMed Google Scholar
179. Nemcovicova I, Zajonc DM. The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding. Acta Crystallogr D Biol Crystallogr. 2014;70(pt 3):851–862.
     View this article via: CrossRef PubMed Google Scholar
180. Veld LF, et al. An IL-10 homologue encoded by human cytomegalovirus is linked with the viral “footprint” in clinical samples. Cytokine. 2024;180:156654.
     View this article via: CrossRef PubMed Google Scholar
181. Kolb P, et al. Human cytomegalovirus antagonizes activation of Fcγ receptors by distinct and synergizing modes of IgG manipulation. Elife. 2021;10:e63877.
     View this article via: CrossRef PubMed Google Scholar
182. Otero CE, et al. Rhesus Cytomegalovirus-encoded Fcgamma-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity [preprint]. https://doi.org/10.1101/2024.02.27.582371 Posted bioRxiv February 28, 2024.
183. Institute of Medicine (U.S.). Committee to Study Priorities for Vaccine Development, et al. Vaccines For the 21st Century: ATool for Decisionmaking. National Academy Press; 2000.
184. Byrne C, et al. Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level. Vaccine. 2022;40(35):5179–5188.
     View this article via: CrossRef PubMed Google Scholar
185. Plotkin SA. Preventing infection by human cytomegalovirus. J Infect Dis. 2020;221(suppl 1):123–127.
     View this article via: PubMed Google Scholar
186. Plotkin SA. Can we prevent congenital infection by cytomegalovirus? Clin Infect Dis. 2023;76(10):1705–1707.
     View this article via: CrossRef PubMed Google Scholar
187. Griffiths PD, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256–1263.
     View this article via: CrossRef PubMed Google Scholar
188. Plotkin SA, et al. The status of vaccine development against the human cytomegalovirus. J Infect Dis. 2020;221(suppl 1):113–122.
     View this article via: PubMed Google Scholar
189. La Rosa C, et al. Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis. Am J Hematol. 2023;98(4):588–597.
     View this article via: CrossRef PubMed Google Scholar
190. Pass RF, et al. A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant. J Infect Dis. 1999;180(4):970–975.
     View this article via: CrossRef PubMed Google Scholar
191. Dasari V, et al. A bivalent CMV vaccine formulated with human compatible TLR9 agonist CpG1018 elicits potent cellular and humoral immunity in HLA expressing mice. PLoS Pathog. 2022;18(6):e1010403.
     View this article via: CrossRef PubMed Google Scholar
192. Berencsi K, et al. A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J Infect Dis. 2001;183(8):1171–1179.
     View this article via: CrossRef PubMed Google Scholar
193. Nelson CS, et al. Human cytomegalovirus glycoprotein b nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization. J Virol. 2020;94(9):e00186-20.
     View this article via: CrossRef PubMed Google Scholar
194. Sabbaj S, et al. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011;203(11):1534–1541.
     View this article via: CrossRef PubMed Google Scholar
195. Schleiss MR, et al. Proceedings of the Conference “CMV Vaccine Development-How Close Are We?” (27-28 September 2023). Vaccines (Basel). 2024;12(11):1231.