Maternal immune correlates of protection from human cytomegalovirus transmission to the fetus after primary infection in pregnancy

2016 ◽  
Vol 27 (2) ◽  
pp. e1921 ◽  
Author(s):  
Daniele Lilleri ◽  
Giuseppe Gerna
Keyword(s):  
Human Cytomegalovirus ◽  
Primary Infection ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
In Pregnancy

scholarly journals Congenital Human Cytomegalovirus Infection: A Narrative Review of Maternal Immune Response and Diagnosis in View of the Development of a Vaccine and Prevention of Primary and Non-Primary Infections in Pregnancy

2021 ◽  
Vol 9 (8) ◽  
pp. 1749
Author(s):  
Giuseppe Gerna ◽  
Chiara Fornara ◽  
Milena Furione ◽  
Daniele Lilleri
Keyword(s):  
Immune Response ◽  
Human Cytomegalovirus ◽  
Primary Infection ◽  
Cytomegalovirus Infection ◽  
Hcmv Infection ◽  
Antiviral Treatment ◽  
Virus Transmission ◽  
Immune Correlates ◽  
Maternal Immune Response ◽  
In Pregnancy

Congenital cytomegalovirus infection (cCMV) may affect about 1% of all newborns all over the world as a result of either a primary or recurrent human cytomegalovirus (HCMV) infection. While about 90% of infants affected by cCMV are asymptomatic at birth, the remaining 10% are symptomatic often with neurodevelopmental impairment and sensorineural hearing loss. In view of identifying the best approach to vaccine prevention of cCMV, this review will examine the most important steps made in the study of the immune response to, and diagnosis of, HCMV infection. The maternal immune response and immune correlates of protection are being partially identified with a partial contribution given by our laboratory. The diagnosis of primary infection is often difficult to achieve in the first three months of pregnancy, which is the time primarily involved in virus transmission to the fetus in association with the most severe symptoms and sequelae. Prevention of cCMV is anticipated by prevention of primary infection in early pregnancy by means of different measures, such as (i) behavioral-educational measures, (ii) immunoglobulin administration, (iii) antiviral treatment with valaciclovir. However, the most promising approach to cCMV prevention appears to be the development of a non-living vaccine, including at least three viral antigens: gB, pentamer complex gHgLpUL128L, and pp65, which have been shown to be able to stimulate both the humoral and the cellular arms of the maternal immune response. Primary HCMV infection may be managed in pregnancy by counseling of the couples involved by a team of specialists that includes virologists, obstetricians, infectivologists and neonatologists.

scholarly journals Human Cytomegalovirus Congenital (cCMV) Infection Following Primary and Nonprimary Maternal Infection: Perspectives of Prevention through Vaccine Development

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 194
Author(s):  
Giuseppe Gerna ◽  
Daniele Lilleri
Keyword(s):  
Human Cytomegalovirus ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Maternal Infection ◽  
Major Step ◽  
Congenital Cytomegalovirus ◽  
Partial Protection ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Hyperimmune Globulin

Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo latency. From a diagnostic standpoint, while the serological criteria for the diagnosis of PI are well-established, those for the diagnosis of NPI are still incomplete. Thus far, a recombinant gB subunit vaccine has provided the best results in terms of partial protection. This partial efficacy was hypothetically attributed to the post-fusion instead of the pre-fusion conformation of the gB present in the vaccine. Future efforts should be addressed to verify whether a new recombinant gB pre-fusion vaccine would provide better results in terms of prevention of both PI and NPI. It is still a matter of debate whether human hyperimmune globulin are able to protect from HCMV vertical transmission. In conclusion, the development of an HCMV vaccine that would prevent a significant portion of PI would be a major step forward in the development of a vaccine for both PI and NPI.

scholarly journals Immune Correlates of Protection Against Human Cytomegalovirus Acquisition, Replication, and Disease

2020 ◽  
Vol 221 (Supplement_1) ◽  
pp. S45-S59 ◽  
Author(s):  
Cody S Nelson ◽  
Ilona Baraniak ◽  
Daniele Lilleri ◽  
Matthew B Reeves ◽  
Paul D Griffiths ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Performance Outcomes ◽  
Solid Organ ◽  
Cell Transplant ◽  
End Points ◽  
Hematopoietic Stem ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Infant Birth

Abstract Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects and an etiology of significant morbidity and mortality in solid organ and hematopoietic stem cell transplant recipients. There is tremendous interest in developing a vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease, yet after nearly a half-century of research and development in this field we remain without such an intervention. Defining immune correlates of protection is a process that enables targeted vaccine/immunotherapeutic discovery and informed evaluation of clinical performance. Outcomes in the HCMV field have previously been measured against a variety of clinical end points, including virus acquisition, systemic replication, and progression to disease. Herein we review immune correlates of protection against each of these end points in turn, showing that control of HCMV likely depends on a combination of innate immune factors, antibodies, and T-cell responses. Furthermore, protective immune responses are heterogeneous, with no single immune parameter predicting protection against all clinical outcomes and stages of HCMV infection. A detailed understanding of protective immune responses for a given clinical end point will inform immunogen selection and guide preclinical and clinical evaluation of vaccines or immunotherapeutics to prevent HCMV-mediated congenital and transplant disease.

scholarly journals Pitfalls in the Serological Diagnosis of Primary Human Cytomegalovirus Infection in Pregnancy Due to Different Kinetics of IgM Clearance and IgG Avidity Index Maturation

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 396
Author(s):  
Antonella Sarasini ◽  
Alessia Arossa ◽  
Maurizio Zavattoni ◽  
Chiara Fornara ◽  
Daniele Lilleri ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Human Cytomegalovirus ◽  
Primary Infection ◽  
Hcmv Infection ◽  
Serological Diagnosis ◽  
Avidity Index ◽  
Igm Antibody ◽  
Igg Avidity ◽  
Kinetics Of ◽  
In Pregnancy

Primary infection occurs when seronegative women are infected by human cytomegalovirus (HCMV). Diagnosis of primary infection is based on the following: antibody seroconversion, presence of IgM and low IgG avidity index (AI), and presence of DNAemia. The kinetics of HCMV-specific IgM antibody and maturation of AI might be very rapid or long-lasting during primary infection, which makes serological diagnosis insidious. The aims of this study were as follows: (i) to report atypical kinetics of HCMV-specific IgM antibody and AI early after onset of primary HCMV infection in a population of pregnant women, and (ii) to assess the frequency of such results. Altogether, 1309 sequential serum samples collected from 465 pregnant women with primary HCMV infection were included in the study. As a general rule, using the LIAISON®CMVIgMII and LIAISON®CMVIgGAvidityII assays, virus-specific IgM antibody levels decreased, while IgG AI increased over time during the first three months after infection onset. However, early clearance of IgM antibody and/or early IgG AI maturation occurred in 46/426 (10.7%) women. In more details, 20/426 (4.7%) and 26/418 (6.2%) women had undetectable IgM antibody or high IgG AI, respectively, when tested within 1–3 months after well-defined infection onset. Twenty sera from as many women with high IgG AI by the LIAISON assay were further tested for IgG AI by VIDAS®CMVIgGAvidityII and Mikrogen recomLineCMVIgG Avidity assays. Comparable results were obtained with VIDAS, whereas 14/20 sera gave low AI with the Mikrogen assay. In conclusion, about 11% of pregnant women undergoing a primary HCMV infection showed misleading serological results. Additional and appropriate testing might help in reducing the risk of missing HCMV primary infection in pregnancy. Furthermore, preconceptional testing should be strongly recommended.

scholarly journals Development of a Vaccine against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 551
Author(s):  
Sara Scarpini ◽  
Francesca Morigi ◽  
Ludovica Betti ◽  
Arianna Dondi ◽  
Carlotta Biagi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Health Concern ◽  
Live Vaccines ◽  
Target Populations ◽  
Immune Correlates ◽  
Common Causes ◽  
The Status ◽  
Life Threatening

Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.

scholarly journals LB20. Valacyclovir to Prevent Vertical Transmission of Cytomegalovirus After Maternal Primary Infection During Pregnancy

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S1002-S1002 ◽  
Author(s):  
Keren Shahar-Nissan ◽  
Joseph Pardo ◽  
Orit Peled ◽  
Irit Krause ◽  
Efraim Bilavsky ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Vertical Transmission ◽  
Primary Infection ◽  
Antiviral Drug ◽  
First Trimester ◽  
Controlled Study ◽  
Therapeutic Drug ◽  
Control Group ◽  
Cmv Infection ◽  
In Pregnancy

Abstract Background Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. The highest risk of fetal injury follows a maternal primary infection early in pregnancy. Despite the potential for severe fetal injury, to date there are no proven means to prevent viral transmission. Valacyclovir is an antiviral drug proven effective in decreasing the risk for CMV infection among transplant recipients. Valacyclovir is safe for use in pregnancy, and concentrates in the amniotic fluid without accumulating. A dose of 8 g/day creates therapeutic drug levels in the amniotic fluid and fetal blood. Methods This is a randomized, double-blind, placebo-controlled study comprising pregnant women with serologic evidence of primary CMV infection during the periconceptional period and first trimester. After informed consent, patients were randomly assigned to a treatment group (8 g/day of Valacyclovir) or control group (placebo). Treatment was initiated at the time of serological detection, and continued until amniocentesis. The primary endpoint was the rate of vertical transmission of CMV—determined by amniotic fluid CMV PCR. Secondary endpoints included evidence of symptomatic congenital CMV infection—in utero or postnatally. Results One hundred women were recruited, 90 were included in the data analysis; 45 patients received Valacyclovir and 45 placebo. There were 2 twin pregnancies, and therefore 92 amniocentesis Amongst the Valacyclovir group, 5 (11.1%) amniocentesis were positive for CMV, compared with 14 (29.8%) in the placebo group (P GLMM = 0.03), corresponding with an odds ratio of 0.29 (95% CI: 0.09–0.90) for vertical CMV transmission. Amongst patients infected during the first trimester, a positive amniocentesis for CMV was significantly (P = 0.02) less likely in the Valacyclovir arm (2/19) compared with placebo (11/23). No significant differences (P = 0.91) in CMV-positive amniocentesis were observed between study arms amongst patients infected periconceptionally. Conclusion Valacyclovir at a dose of 8 g/day is effective in reducing the rate of fetal CMV infection following early maternal primary infection during pregnancy. The drug reduces the rate of fetal infection by 71%. Disclosures All authors: No reported disclosures.

scholarly journals Identifying Immune Correlates of Protection Against Plasmodium falciparum Through a Novel Approach to Account for Heterogeneity in Malaria Exposure

2017 ◽  
Vol 66 (4) ◽  
pp. 586-593 ◽  
Author(s):  
Aida Valmaseda ◽  
Eusebio Macete ◽  
Augusto Nhabomba ◽  
Caterina Guinovart ◽  
Pedro Aide ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Novel Approach ◽  
Malaria Exposure
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