Intrauterine Transmission of Cytomegalovirus to Infants of Women with Preconceptional Immunity

Boppana, Suresh B.; Rivera, Lisa B.; Fowler, Karen B.; Mach, Michael; Britt, William J.

doi:10.1056/nejm200105033441804

Cited by 663 publications

(384 citation statements)

References 29 publications

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“…In addition to the limited sampling of genomic diversity inherent in restriction fragment length polymorphism (RFLP) analyses, the extensive in vitro amplification of viral isolates required prior to these analyses introduced a range of potential biases secondary to passage of clinical viral isolates. As DNA sequencing of individual viral genes became more commonplace and the genetic diversity of isolates of HCMV were observed, reinfection (superinfection) of immunocompetent women with new strains of HCMV were reported (28)(29)(30). Reinfection with an antigenically distinct strain of virus in these studies could be demonstrated by development of corresponding serologic reactivity to the new viral strain and confirmed by recovery of viruses encoding new antigenic determinants (28,30).…”

Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 95%

“…Reinfection with an antigenically distinct strain of virus in these studies could be demonstrated by development of corresponding serologic reactivity to the new viral strain and confirmed by recovery of viruses encoding new antigenic determinants (28,30). Importantly, reinfection of seroimmune pregnant women was also associated with transmission of the newly acquired virus to the fetus (28,30). Similarly, more controlled studies of rhesus macaques have clearly demonstrated that macaques with robust preexisting adaptive immunity to rhesus CMV could be readily reinfected with laboratory and wild strains of rhesus CMV (31-33).…”

Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 96%

“…As DNA sequencing of individual viral genes became more commonplace and the genetic diversity of isolates of HCMV were observed, reinfection (superinfection) of immunocompetent women with new strains of HCMV were reported (28)(29)(30). Reinfection with an antigenically distinct strain of virus in these studies could be demonstrated by development of corresponding serologic reactivity to the new viral strain and confirmed by recovery of viruses encoding new antigenic determinants (28,30). Importantly, reinfection of seroimmune pregnant women was also associated with transmission of the newly acquired virus to the fetus (28,30).…”

Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 99%

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Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

Britt

2017

J Virol

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153

158

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Human cytomegalovirus (HCMV) is the most common viral infection acquired by the developing human fetus and can result in damage to the developing central nervous system. Although vaccine development to modify this congenital infection is ongoing, the unique epidemiology of maternal HCMV infections appears discordant with strategies for vaccine development. Several characteristics of congenital HCMV infections suggest that the efficacy of vaccines designed to induce responses similar to those that follow natural infection will be limited.

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Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 95%

Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 96%

Section: Hcmv Infections During Pregnancy (I) Maternal Immunity and mentioning

confidence: 99%

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Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

Britt

2017

J Virol

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153

158

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“…In order to determine whether the vaccine-derived NAb confer similar potency than previously described human NAb (32) to prevent host cell entry, we evaluated the inhibitory antibody concentration (IC 50 ) that blocked 50% HCMV infection of ARPE-19 EpC, HUVEC EnC, or MRC-5 FB using a standard microneutralization assay. We tested neutralization against HCMV strains TB40/E and TR to evaluate whether sequence variation in the gH component influences the potency of the NAb to neutralize HCMV (36,69). Neutralization potency of HCMV hyperimmune globulin (CMV-HIG) was eval- …”

Section: Mva-pc Vaccine-derived Nab Recognize Epitopes Of the Pc And mentioning

confidence: 99%

Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

Chiuppesi

Wussow

Johnson

et al. 2015

J Virol

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127

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Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/ 131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells. IMPORTANCEAs a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based on a widely used, safe, and well-characterized poxvirus vector platform to elicit potent and durable neutralizing antibody (NAb) responses targeting the HCMV envelope pentamer complex (PC), which has been suggested as a critical component for a vaccine to prevent congenital HCMV infection. With this work, we confirm that the NAb elicited by the vaccine vector have properties that are similar to those of human NAb isolated from individuals chronically infected with HCMV. In addition, we show that PCspecific NAb have potent ability to prevent infection of key placental cells that HCMV utilizes to cross the fetal-maternal interface, suggesting that NAb targeting the PC may be essential to prevent HCMV vertical transmission. Human cytomegalovirus (HCMV) is the most common infectious cause of permanent births defects worldwide, often resulting in auditory and cognitive abnormalities and in rare cases even in multiorgan failure and death (1-4). Congenital HCMV infection occurs in 0.05 to 1% of all pregnancies, and 10 to 25% of congenitally infected newborns d...

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“…Affected children can have permanent neurological complications, including hearing loss, visual impairment and mental retardation [1][2][3] . In Australia, 57% of women are seronegative and at risk for primary infection and transmission of virus to the fetus during pregnancy 4 .…”

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confidence: 99%

Cytomegalovirus infection and pathogenesis in the human placenta

2015

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As shown in Figure 1, the human placenta is composed of chorionic villi bathed in maternal blood and villi that anchor the placenta in the uterine wall (decidua), attaching the fetus to the mother (panel a1). The individual chorionic villus contains a connective core with blood vessels that carry substances to the fetal circulation (panel a2). Placentation is a stepwise process whereby villus cytotrophoblasts (vCTB) attached to the basement membrane as a polarised epithelium leave the membrane to differentiate along one of two independent pathways depending on their location. In floating villi, they fuse to form a multinucleate synctiotrophoblast (STB) covering attached at one end to the tree-like fetal portion of the placenta. The rest of the villus floats in a stream of maternal blood, which optimises exchange of substances between the maternal and fetal circulation. In the pathway that gives rise to anchoring villi, cytotrophoblasts aggregate into cell columns of non-polarised mononuclear cells that attach to and then invade the uterine wall (iCTBs).

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Intrauterine Transmission of Cytomegalovirus to Infants of Women with Preconceptional Immunity

Abstract: In women who are seropositive for CMV, reinfection with a different strain of CMV can lead to intrauterine transmission and symptomatic congenital infection.

Cited by 663 publications

References 29 publications

Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

Cytomegalovirus infection and pathogenesis in the human placenta

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