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.

Milena Furione,Giuseppe Gerna,Daniele Lilleri,Chiara Fornara

doi:10.3390/microorganisms9081749

Abstract

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.

Highlights

Human cytomegalovirus (HCMV) or human herpesvirus-5 is a human herpesvirus that is widespread in all five continents and is generally responsible for asymptomatic or mildly symptomatic infections in an immunocompetent host but may cause severe multi-organ disease in an immunocompromised host, such as HIV-1-infected patients and solid-organ/hemopoietic stem cell-transplanted patients
The pooled rates of fetal damage in 796 fetuses from the 10 studies at the same time were 28.8%, 19.3%, 0.9%, and 0.4% at the periconception, first, second and third trimester of pregnancy, respectively. These findings allowed the authors to conclude that, while the congenital HCMV (cCMV) rate increased with the progression of pregnancy, the rate of severe fetal pathology was very rare after maternal primary infection (PI) occurring in the 2nd–3rd trimester of pregnancy [1,2]
While for some time pre-pregnancy maternal immunity was considered to be associated with a lower rate of severe permanent sequelae, other reports have shown that the frequency was comparable in infants with cCMV born to mothers with PI or non-primary infection (NPI) [7,12,13,14]

Summary

Introduction

Human cytomegalovirus (HCMV) or human herpesvirus-5 is a human herpesvirus that is widespread in all five continents and is generally responsible for asymptomatic or mildly symptomatic infections in an immunocompetent host but may cause severe multi-organ disease in an immunocompromised host, such as HIV-1-infected patients and solid-organ/hemopoietic stem cell-transplanted patients. The most severe outcome of HCMV infection may occur in pregnant women with HCMV primary infection (PI) or even with non-primary infection (NPI) (reactivation or re-infection). The result of HCMV infection acquired during pregnancy may be HCMV transmission to the fetus in about 40% of the cases of PI. In cases of NPI of a seroimmune pregnant woman with a different HCMV strain, the incidence of congenital HCMV (cCMV). Microorganisms 2021, 9, 1749 mostly asymptomatic at birth, but could present with more or less severe sequelae in the following months/years. We will briefly discuss some aspects related to the epidemiology, diagnosis, the maternal immune response and the immune correlates of protection against virus transmission to the fetus in view of identifying the most effective approach to vaccine prevention of cCMV. Since our group in Pavia, Italy, has been involved in the study of cCMV for almost 40 years, an important part of the findings reported in this review originates from our daily research and clinical findings

Epidemiology

Clinical Features of cCMV

Humoral Immunity

Cellular Immunity

Diagnosis of Maternal Infection

Genotype-specific

Prenatal Diagnosis of cCMV

Prevention

Management of Pregnancy and Counseling

Findings

Conclusions and Final Remarks