A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimera Vaccines in Cytomegalovirus-Seronegative Men.

BACKGROUND: Human cytomegalovirus (HCMV) infection causes disease in newborns and transplant recipients. A HCMV vaccine (Towne) protects transplant recipients. METHODS: The genomes of Towne and the nonattenuated Toledo strain were recombined, yielding 4 Towne/Toledo chimera vaccines. Each of 36 HCMV-seronegative men received 1 subcutaneous dose of 10, 100, or 1000 plaque-forming units (PFU) in cohorts of 3. Safety and immunogenicity were evaluated over 12 weeks after immunization and for 52 weeks for those who seroconverted. RESULTS: There were no serious local or systemic reactions. No subject had HCMV in urine or saliva. For chimera 3, none of 9 subjects seroconverted. For chimera 1, 1 of 9 seroconverted (the seroconverter received 100 PFU). For chimera 2, 3 subjects seroconverted (1 received 100 PFU, and 2 received 1000 PFU). For chimera 4, 7 subjects seroconverted (1 received 10 PFU, 3 received 100 PFU, and 3 received 1000 PFU). All 11 seroconverters developed low but detectable levels of neutralizing activity. CD4+ T-cell responses were detectable in 1 subject (who received 100 PFU of chimera 4). Seven subjects receiving chimera 2 or 4 had detectable CD8+ T-cell responses to IE1; 3 responded to 1-2 additional antigens. CONCLUSIONS: The Towne/Toledo chimera vaccine candidates were well tolerated and were not excreted. Additional human trials of chimeras 2 and 4 are appropriate. CLINICAL TRIALS REGISTRATION: NCT01195571.

Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight.

BACKGROUND: Cytomegalovirus (CMV) hyperimmune globulin (HIG) may be helpful after a primary maternal CMV infection during pregnancy as a therapy for infected fetuses or to prevent maternal-to-fetus transmission of CMV. Although immunoglobulins administered during pregnancy appear safe, previous studies have not monitored HIG for a possible effect on duration of gestation and birth weight. METHODS: We used clinical data on 358 women with a primary CMV infection during pregnancy, 164 of whom received one or more infusions of HIG. RESULTS: The average birth weight of the 358 infants was 3076 g and the average gestational age at delivery for 351 women was 38.2 weeks. After adjusting for potential confounding variables, the only factor associated with low birth weight and the duration of gestation was the presence of symptoms at birth. The receipt of HIG was not associated with either a diminished birth weight or a reduced duration of pregnancy. The receipt of multiple doses of HIG (range 1-8) was significantly correlated with an increase in birth weight (p=0.006) and gestational age at delivery (p=0.014). This correlation was also significant for all asymptomatic infants and for infants whose mothers received multiple doses of HIG to prevent fetal infection. CONCLUSION: HIG administration during pregnancy is not associated with either diminished gestation or decreased birth weight and may enhance these parameters among women who receive multiple doses starting in early gestation.

Prevention of child-to-mother transmission of cytomegalovirus among pregnant women.

OBJECTIVE: To determine if protective behavior prevents child-to-mother transmission of cytomegalovirus (CMV) during pregnancy. STUDY DESIGN: We studied 166 seronegative mothers (94% white women; mean age, 33 years) with a child <36 months of age attending a day care facility. Mothers, either pregnant or attempting pregnancy, were randomly assigned by day care center to either a control or intervention group. Mothers in the intervention group received instructions for hand washing, glove use, and for avoiding types of intimate contact with their child. The control group received no instructions or information about their serologic status or whether their child was shedding CMV. RESULTS: In the intervention group, 7.8% of women (9 of 115) seroconverted, as did 7.8% of women (4 of 51) in the control group. Two independent predictors of maternal infection were (1) a child shedding and (2) a mother attempting pregnancy at enrollment. For 41 women attempting pregnancy at enrollment with a child shedding CMV, 10 of 24 became infected compared with only 1 of 17 women who were already pregnant at enrollment ( P = .008). CONCLUSIONS: For seronegative women who already know they are pregnant, intervention may be highly effective for preventing CMV acquisition.

Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood.

Human cytomegalovirus (CMV) establishes persistent infection, with control of replication thought to be mediated by CMV-specific CD8 T cells. Primary CMV infection commonly affects young children and causes prolonged viral shedding in saliva and urine. We investigated whether this virus-host interaction pattern reflects a developmental deficiency of antiviral CD8 T cell-mediated immunity during childhood. CMV-specific CD8 T cell responses in asymptomatic children with active infection were not different from adults with recent or long-term infection in frequency and functional analyses. High urine CMV concentrations were detected, despite these CMV-specific CD8 T cell responses. We conclude that delayed resolution of primary CMV infection in young children is not caused by a deficient CMV-specific CD8 T cell response. Because these healthy children continue to have local CMV replication, we suggest that CD8 T cells may function primarily to prevent symptomatic, disseminated disease.

Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children.

Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4(+) T cells that produced IFN-gamma than did adults. These differences in CD4(+) T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-gamma production by CD8(+) T cells. The IFN-gamma-producing CD4(+) T cells of children or adults that were reactive with CMV Ags were mainly the CCR7(low) cell subset of memory (CD45R0(high)CD45RA(low)) cells. The decreased IFN-gamma response to CMV in children was selective, because their CCR7(low) memory CD4(+) T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4(+) T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4(+) T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4(+) T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.