Study of the Transmission of Cytomegalovirus (CMV) Infection From Mother to Foetus

Not Applicable

Completed

Conditions: Cytomegalovirus Infections
Infections, Cytomegalovirus

Interventions: Procedure: Blood sample
Procedure: Cord blood sample
Procedure: Saliva swab
Procedure: Urine sampling
Procedure: Vaginal swab

Registration Number: NCT01251744

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study is designed to evaluate maternal virological and immunological parameters to determine their ability to predict congenital cytomegalovirus (CMV) infection. When a pregnant woman is infected with CMV, her immune system (which protects her from infection) is activated and the virus can be found in the woman's bodily fluids (blood, saliva, urine, vaginal secretions). The aim of this study is to find out if there is a link between either the pregnant woman's immune response or the presence of the virus in these bodily fluids and the child/foetus being infected with the virus.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 160

Inclusion Criteria

Subjects who the investigator believes that they can and will comply with the requirements of the protocol .
A pregnant female, 18 years of age or older at the time of study enrolment.
Women with confirmed primary CMV infection.
Written informed consent obtained from the subject.

Exclusion Criteria

Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to study entry.
Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational pharmaceutical product.
Previous vaccination against CMV infection.
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history or physical examination
Major congenital defects, serious chronic illness or organ transplantation.
Administration of immunoglobulins and/or any blood products within the three months preceding study enrolment or during the pregnancy.
Documented Human immunodeficiency virus (HIV)-positive subject.
Gestational age of more than 34 weeks, as determined by foetal ultrasound.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CMV Mothers' Group	Vaginal swab	Pregnant subjects with confirmed primary CMV infection.
CMV Newborns' Group	Saliva swab	Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.
CMV Mothers' Group	Blood sample	Pregnant subjects with confirmed primary CMV infection.
CMV Mothers' Group	Cord blood sample	Pregnant subjects with confirmed primary CMV infection.
CMV Mothers' Group	Urine sampling	Pregnant subjects with confirmed primary CMV infection.
CMV Newborns' Group	Urine sampling	Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.
CMV Mothers' Group	Saliva swab	Pregnant subjects with confirmed primary CMV infection.
CMV Newborns' Group	Blood sample	Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.
CMV Newborns' Group	Vaginal swab	Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.
CMV Newborns' Group	Cord blood sample	Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.

Primary Outcome Measures

Name	Time	Method
Anti-glycoprotein B (gB) Immunoglobulin Type G (IgG) Antibody Concentrations	At Month 0	Anti-gB IgG concentrations were assessed by ELISA, presented as geometric mean concentrations (GMCs) and expressed in ELISA units per milliliter (EU/mL). The cut-off value was greater than or equal to (≥) 54 EU/mL.
Anti-gB IgG Antibody Concentrations	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Anti-gB IgG concentrations were assessed by ELISA, presented as geometric mean concentrations (GMCs) and expressed in ELISA units per milliliter (EU/mL). The cut-off value was greater than or equal to (≥) 54 EU/mL.
Descriptive Statistics of the Anti-glycoprotein B (gB) Immunoglobulin Type G (IgG) Avidity Index	At Month 0	The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Descriptive Statistics of the Anti-gB IgG Avidity Index	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
CMV-specific Cluster of Differentiation 4 (CD4) T-cell Frequencies	At Month 0	Descriptive statistics of the frequency of CMV-specific CD4 T cells expressing at least two markers among: cluster of differentiation 40 ligand (CD40L), interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), as assessed by Intracellular Cytokine Staining \[ICS\], by stimulating agent (among Human Cytomegalovirus \[HCMV\] immediate-early gene \[IE1\] antigen, HCMV glicoprotein B \[gB\] antigen, HCMV lysate antigen and HCMV pp65 antigen).
CMV-specific CD4 T-cell Frequencies	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Descriptive statistics of the frequency of CMV-specific CD4 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining \[ICS\], by stimulating agent (among immediate-early gene \[IE1\] antigen, glicoprotein B \[gB\] antigen, CMV lysate antigen and CMV pp65 antigen).
CMV-specific Cluster of Differentiation 8 (CD8) T-cell Frequencies	At Month 0	Descriptive statistics of the frequency of CMV-specific CD8 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining \[ICS\], by stimulating agent (among immediate-early gene \[IE1\] antigen, glicoprotein B \[gB\] antigen, CMV lysate antigen and CMV pp65 antigen).
CMV-specific CD8 T-cell Frequencies	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Descriptive statistics of the frequency of CMV-specific CD8 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining \[ICS\], by stimulating agent (among immediate-early gene \[IE1\] antigen, glicoprotein B \[gB\] antigen, CMV lysate antigen and CMV pp65 antigen).
CMV-specific Proliferating Cluster of Differentiation (CD4) T Cells Frequencies	At Month 0	Labelled cells were quantified by flow cytometry, by stimulating agent (among immediate-early gene \[IE1\] antigen, glicoprotein B \[gB\] antigen, CMV lysate antigen and CMV pp65 antigen).
CMV-specific Proliferating CD4 T Cells Frequencies	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Labelled cells were quantified by flow cytometry, by stimulating agent (among immediate-early gene \[IE1\] antigen, glicoprotein B \[gB\] antigen, CMV lysate antigen and CMV pp65 antigen). Note: Results were retrieved by subtracting the background without imputing the negative and zero values, this generated negative values.
Concentrations of Anti-CMV Tegument Protein Immunoglobulin G (IgG) Antibodies	At Day 0 = study entry	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
Anti-CMV Tegument Protein Immunoglobulin G (IgG) Antibody Concentrations	At Month 2	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
Concentrations of Anti-CMV Tegument Protein IgG Antibodies	At Month 4	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
Anti-CMV Tegument Protein IgG Antibody Concentrations	At Month 6	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
Concentrations of Anti-CMV IgG Antibodies	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
Descriptive Statistics of the Anti-CMV Tegument Protein Globulin Type B (gB) Immunoglobulin G (IgG) Avidity, by Congenital Infection Status	At Day 0 = study entry	Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Descriptive Statistics of the Anti-CMV Tegument Protein gB Immunoglobulin G (IgG) Avidity, by Congenital Infection Status	At Month 2	Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Descriptive Statistics of the Anti-CMV Tegument Protein gB IgG Avidity, by Congenital Infection Status	At Month 4	Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Descriptive Statistics of the Anti-CMV Tegument Protein Globulin Type B (gB) IgG Avidity, by Congenital Infection Status	At Month 6	Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Anti-CMV Tegument Protein Globulin Type B (gB) Immunoglobulin G (IgG) Avidity Descriptive Statistics, by Congenital Infection Status	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast)	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells)	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
Number of CMV DNA Copies in Saliva, Urine, Blood or Vaginal Secretions	At Month 0	The assessment focused on the presence of CMV DNA copies (by Quantitative Polymerase Chain Reaction \[qPCR\]) in saliva, urine, blood and vaginal secretions every month from study entry to, and including, pregnancy conclusion.
Number of CMV DNA Copies in Saliva, in Urine and in Blood or Vaginal Secretions	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	The assessment focused on the presence of CMV DNA copies (by Quantitative Polymerase Chain Reaction \[qPCR\]) in saliva, urine and blood every month from study entry to, and including, pregnancy conclusion.
Descriptive Statistics of the Anti-CMV Immunoglobulin Type M (IgM) Status	At Month 0	Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay \[ELISA\], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
Descriptive Statistics of the Anti-CMV IgM Status	At Month 2	Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay \[ELISA\], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
Descriptive Statistics of the Anti-Cytomegalovirus (Anti-CMV) Immunoglobulin Type M (IgM) Status	At Month 4	Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay \[ELISA\], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
Anti-CMV Immunoglobulin Type M (IgM) Status, Descriptive Statistics	At Month 6	Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay \[ELISA\], with respect to positive and negative subjects.
Descriptive Statistics for the Anti-CMV IgM Status	At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination)	Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay \[ELISA\], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
Number of Subjects With Any Cytomegalovirus (CMV) Congenital Infection	At Month 0	The CMV congenital infections were assessed in newborns and foetuses of subjects who had a confirmed primary CMV infection during pregnancy.
Number of Subjects With CMV Presence in the Urine	Within 10 days post-delivery (Days 0-9)	Evidence of infection in urine was assessed by culture or by Polymerase Chain Reaction (PCR).
Number of Subjects With CMV Presence in the Amniotic Fluid	Within 10 days post-delivery (Days 0-9)	Evidence of infection in the amniotic fluid was assessed by culture or by Polymerase Chain Reaction (PCR).
Evidence of CMV DNA or CMV Inclusions in Tissues of an Aborted or Stillborn Foetus	Within 10 days post-delivery (Days 0-9)