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Thesis (Ed.M.)--Boston Universit

Screening for Cytomegalovirus during Pregnancy

The epidemiology and pathogenesis of CMV infections among pregnant women have been intensely studied over the last three decades. This paper highlights recent developments that make either universal or limited serologic screening for CMV during pregnancy potentially attractive. The developments include an understanding of the pathogenesis of CMV infections, a knowledge of high-risk women, the availability of accurate methods for the serologic diagnosis of a primary CMV infection using either single or serial blood samples, accurate methods for the diagnosis of fetal infection via amniotic fluid, sensitive fetal and placental indicators for neonatal outcomes, and the availability of potentially effective interventions

Cytomegalovirus and Child Day Care

Abstract To determine whether day-care workers acquire cytomegalovirus infection from the children they care for, we studied 610 women employed at 34 day-care centers over two years. Forty-one percent of the caretakers were seropositive for cytomegalovirus. After adjustment for the effects of race, marital status, and age on seropositivity, the women who cared for children younger than two years of age had a significantly higher seropositivity rate (46 percent) than the women who cared for children older than two years of age (35 percent) (relative risk, 1.29; 95 percent confidence interval, 1.05 to 1.57; P\u3c0.02). Of 202 initially seronegative caretakers (observed for an average of 305 days per woman), 19 seroconverted, for an annual seroconversion rate of 11 percent. This rate was significantly higher than the 2 percent annual rate of seroconversion among 229 seronegative women (11 of whom seroconverted) in a comparison group of female hospital employees observed for an average of 781 days per woman (relative risk, 5.0; 95 percent confidence interval, 2.4 to 10.5; P We conclude that workers in day-care centers may acquire cytomegalovirus infection from the children in their care and that this risk is significantly greater among those who care for children less than two years of age. (N Engl J Med 1989;321:1290–6.

Passive immunization during pregnancy for congenital cytomegalovirus infection

BACKGROUND Currently, there is no effective intervention for a primary cytomegalovirus (CMV) infection during pregnancy. METHODS We studied pregnant women with a primary CMV infection. The therapy group comprised women whose amniotic fluid contained either CMV or CMV DNA and who were offered intravenous CMV hyperimmune globulin at a dose of 200 U per kilogram of maternal weight. A prevention group, consisting of women with a recent primary infection before 21 weeks\u27 gestation or who declined amniocentesis, was offered monthly hyperimmune globulin (100 U per kilogram intravenously). RESULTS In the therapy group, 31 women received hyperimmune globulin, only 1 (3 percent) of whom gave birth to an infant with CMV disease (symptomatic at birth and handicapped at two or more years of age), as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio, 0.02; 95 percent confidence interval, ¡∞ to 0.15; P\u3c0.001). In the prevention group, 37 women received hyperimmune globulin, 6 (16 percent) of whom had infants with congenital CMV infection, as compared with 19 of 47 women (40 percent) who did not receive hyperimmune globulin. Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio, 0.32; 95 percent confidence interval, 0.10 to 0.94; P=0.04). Hyperimmune globulin therapy significantly (P\u3c0.001) increased CMV-specific IgG concentrations and avidity and decreased natural killer cells and HLA-DR+ cells and had no adverse effects. CONCLUSIONS Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate

Lack of autoantibody production associated with cytomegalovirus infection

To confirm an association between cytomegalovirus (CMV) infection and the presence of antibodies to Smith (Sm), to ribonucleoprotein (RNP), and to a component of the U1 ribonucleoproteins (U1-70 kD), we measured antibodies to these protein antigens using an enzyme immunoassay and an immunoblot. The antibodies were measured in the sera of 80 healthy subjects, one-half of whom were naturally CMV seropositive and one-half were CMV seronegative, and in eight subjects immunized with a live attenuated strain of CMV. None of the vaccinees developed antibodies to Sm, to RNP, or to U1-70 kD at either 4 or 12 months after immunization. Additionally, there was no statistically significant association between levels of antibodies to Sm or to RNP and between sera obtained from vaccinees, natural CMV seropositive individuals, and CMV seronegative individuals. One CMV seropositive serum and one CMV seronegative serum tested positive for antibodies to U1-70 kD. These data indicate that neither wild-type infection nor the live-attenuated Towne vaccine frequently induce autoantibody production

Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease

Background. Serological testing for primary maternal cytomegalovirus (CMV) infection during pregnancy is not routine, but ultrasound studies are routine. Therefore, we evaluated placental thickening in women with primary CMV infection during pregnancy. Methods. The study included 92 women with primary CMV infection during pregnancy and 73 CMV-seropositive pregnant women without primary CMV infection. Neonatal CMV transmission was determined by CMV culture of urine samples. Thirty-two women were treated with CMV hyperimmune globulin to either prevent or treat intrauterine CMV infection. Maximal placental thickness was measured by longitudinal (nonoblique) scanning with the ultrasound beam perpendicular to the chorial dish. Programmed placental ultrasound evaluations were performed from 16 to 36 weeks of gestation. Results. At each measurement between 16 and 36 weeks of gestation, women with primary CMV infection who had a fetus or newborn with CMV disease had placentas that were significantly thicker than those of women with primary CMV infection who did not have a diseased fetus or newborn (P <.0001); the latter group, in turn, P <.0001 had placentas that were significantly thicker than those of seropositive control subjects (P <.0001). For both women P <.0001 with and women without diseased fetuses or newborns, receipt of hyperimmune globulin after primary CMV infection was associated with statistically significant reductions in placental thickness (P <.001). Placental vertical P <.001 thickness values, which are predictive of primary maternal infection, were observed at each measurement from 16 to 36 weeks of gestation, and cutoff values ranged from 22 mm to 35 mm, with the best sensitivity and specificity at 28 and 32 weeks of gestation. Conclusions. Primary maternal CMV infection and fetal or neonatal disease are associated with sonographically thickened placentas, which respond to administration of hyperimmune globulin. These observations suggest that many of the manifestations of fetal and neonatal disease are caused by placental insufficiency

Bacterial Artificial Chromosome Clones of Viruses Comprising the Towne Cytomegalovirus Vaccine

Bacterial artificial chromosome (BAC) clones have proven invaluable for genetic manipulation of herpesvirus genomes. BAC cloning can also be useful for capturing representative genomes that comprise a viral stock or mixture. The Towne live attenuated cytomegalovirus vaccine was developed in the 1970s by serial passage in cultured fibroblasts. Although its safety, immunogenicity, and efficacy have been evaluated in nearly a thousand human subjects, the vaccine itself has been little studied. Instead, genetic composition and in vitro growth properties have been inferred from studies of laboratory stocks that may not always accurately represent the viruses that comprise the vaccine. Here we describe the use of BAC cloning to define the genotypic and phenotypic properties of viruses from the Towne vaccine. Given the extensive safety history of the Towne vaccine, these BACs provide a logical starting point for the development of next-generation rationally engineered cytomegalovirus vaccines

Cytomegalovirus Infections among African-Americans

<p>Abstract</p> <p>Background</p> <p>Since African-Americans have twice the prevalence of cytomegalovirus (CMV) infections as age-matched Caucasians we sought to determine the ages and possible sources of infection of African-American children.</p> <p>Methods</p> <p>Subjects were 157 African-American healthy children and adolescents and their 113 household adults in Richmond VA. Families completed a questionnaire, provided saliva for antibody testing, and adolescents were interviewed regarding sexual activity.</p> <p>Results</p> <p>Regardless of age CMV seropositivity was not associated with gender, breast feeding, health insurance, sexual activity, or household income, education, or size. In the final regression model, prior CMV infection in adults was over two-fold higher than in children (chi-square = 18.8, p < 0.0001). At one year of age the CMV seropositivity rate was 11% (95%CI = 4% – 24%) and increased 1.8% each year until age 13 years. Between ages 13 and 20 years the CMV seropositivity rate remained between 22% and 33%. For adults, the CMV seropositivity rate was 84% in 21 year olds (95%CI = 69%–.92%). There was no association between CMV infections of the children and their mothers but CMV infections among siblings were associated.</p> <p>Conclusion</p> <p>We observed that African-American children had CMV seroprevalence rates by age 20 years at less than one-half of that of their adult mothers and caregivers. Sibling-to-sibling transmission was a likely source of CMV infections for the children. The next generation of African-American women may be highly susceptible to a primary CMV infection during pregnancy and may benefit from a CMV vaccine.</p

Regression of fetal cerebral abnormalities by primary cytomegalovirus infection following hyperimmunoglobulin therapy

Objective To assess the effects of maternal and intra-amniotic hyperimmunoglobulin (HIG) infusions among cytomegalovirus (CMV) infected fetuses with ultrasound abnormalities following a primary CMV infection. Patients and Methods The subjects were fetuses with CMV-associated cerebral and other ultrasound abnormalities. Three mothers were treated with HIG infusions during pregnancy and two were untreated. Fetal ventricle size, organ echodensity and placental thickness were measured by ultrasound before and after HIG infusions. The children were evaluated between 3 and 7 years of age. Results The ventriculomegaly of all three fetuses of HIG-treated mothers regressed and the ascites, hepatic echodensities, periventricular echodensities, and intestinal echodensities disappeared. Their sensorial, mental and motor development was normal at 4, 4.7, and 7 years of age. In contrast, both infants born of untreated mothers had signs and symptoms of severe CMV cerebropathy. Conclusion The outcomes of the infants born to HIG-treated mothers support the efficacy of HIG as a treatment for CMV-infected fetuses with ultrasound cerebral abnormalities. Copyright (C) 2008 John Wiley & Sons, Ltd

Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen-the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains. IMPORTANCE HCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen-the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site-specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies