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Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys.

ABSTRACT: Human cytomegalovirus (HCMV) is the most common congenital infection and a known cause of microcephaly, sensorineural hearing loss, and cognitive impairment among newborns worldwide. Natural maternal HCMV immunity reduces the incidence of congenital infection, but does not prevent the disease altogether. We employed a nonhuman primate model of congenital CMV infection to investigate the ability of preexisting antibodies to protect against placental CMV transmission in the setting of primary maternal infection and subsequent viremia, which is required for placental virus exposure. Pregnant, CD4+ T cell-depleted, rhesus CMV-seronegative (RhCMV-seronegative) rhesus monkeys were treated with either standardly produced hyperimmune globulin (HIG) from RhCMV-seropositive macaques or dose-optimized, potently RhCMV-neutralizing HIG prior to intravenous challenge with an RhCMV mixture. HIG passive infusion provided complete protection against fetal loss in both groups. The dose-optimized, RhCMV-neutralizing HIG additionally inhibited placental transmission of RhCMV and reduced viral replication and diversity. Our findings suggest that the presence of durable and potently neutralizing antibodies at the time of primary infection can prevent transmission of systemically replicating maternal RhCMV to the developing fetus, and therefore should be a primary target of vaccines to eliminate this neonatal infection.

SUBMITTER: Nelson CS

PROVIDER: S-EPMC5499366 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys.

Nelson Cody S CS Cruz Diana Vera DV Tran Dollnovan D Bialas Kristy M KM Stamper Lisa L Wu Huali H Gilbert Margaret M Blair Robert R Alvarez Xavier X Itell Hannah H Chen Meng M Deshpande Ashlesha A Chiuppesi Flavia F Wussow Felix F Diamond Don J DJ Vandergrift Nathan N Walter Mark R MR Barry Peter A PA Cohen-Wolkowiez Michael M Koelle Katia K Kaur Amitinder A Permar Sallie R SR

JCI insight 20170706 13

Human cytomegalovirus (HCMV) is the most common congenital infection and a known cause of microcephaly, sensorineural hearing loss, and cognitive impairment among newborns worldwide. Natural maternal HCMV immunity reduces the incidence of congenital infection, but does not prevent the disease altogether. We employed a nonhuman primate model of congenital CMV infection to investigate the ability of preexisting antibodies to protect against placental CMV transmission in the setting of primary mate ...[more]

PMID: 28679960

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Project description:BackgroundAn understanding of the correlation between maternal immunity and congenital cytomegalovirus (CMV) infection is critical for informing the design and evaluation of an effective maternal vaccine. This study aimed to quantitatively measure the protective effect of pre-existing maternal immunity against congenital CMV (cCMV) infection.MethodsA mother-child cohort study was conducted in three maternal and child health hospitals in China from 2015 to 2018. Pregnant women were consecutively enrolled, and anti-CMV pp150 IgG concentration at early, middle and late gestational ages were evaluated. Their newborns were screened for cCMV infection by CMV-DNA testing of saliva and urine.FindingsIn total, 6729 pregnant women were enrolled, and 6602 of them (98·11%) were positive for CMV IgG at their early gestational age visit (median time: 13 gestational weeks (GW); time range: 6-25 GW). In total, 6228 live newborns were born to seropositive mothers, and 48 (0·77%) of these infants were diagnosed with cCMV infection. The geometric mean concentration (GMC) of CMV IgG at an early gestational age in the women who delivered cCMV-positive newborns (i.e., the transmitters) was 8·54 IU/mL; this was significantly lower than the GMC in the non-transmitters (11·01 IU/mL; P=0·04). In early gestation, the risk of cCMV infection decreased as maternal IgG antibody levels increased (P=0·020); however, the same was not true in middle or late gestation (P>0·05). Using receiver operating characteristic analysis, a CMV IgG concentration of 12·83 IU/mL was established as the optimal diagnostic threshold. Compared to lower levels of CMV IgG (<12·83 IU/mL) in seropositive pregnant women, higher maternal CMV IgG levels (≥12·83 IU/mL) were associated with a 50% reduction in cCMV infection risk in infants (relative risk=0·50; 95% confidence interval: 0·27-0·93; P=0·028).InterpretationFor seropositive women, a higher level of CMV IgG at an early gestational age is associated with a lower risk of cCMV infection in their newborns.FundingNational Natural Science Foundation of China; Science and Technology Key Project in Fujian Province; Merck Sharp & Dohme Corp., Kenilworth, NJ, USA; Fieldwork Funds for graduate students of Xiamen University.

Project description:Envelope protein-targeted vaccines for flaviviruses are limited by concerns of antibody-dependent enhancement (ADE) of infections. Nonstructural protein 1 (NS1) provides an alternative vaccine target that avoids this risk since this protein is absent from the virion. Beyond its intracellular role in virus replication, extracellular forms of NS1 function in immune modulation and are recognized by host-derived antibodies. The rational design of NS1-based vaccines requires an extensive understanding of the antigenic sites on NS1, especially those targeted by protective antibodies. Here, we isolated human monoclonal antibodies (MAbs) from individuals previously naturally infected with WNV, mapped their epitopes using structure-guided mutagenesis, and evaluated their efficacy in vivo against lethal WNV challenge. The most protective epitopes clustered at three antigenic sites that are exposed on cell surface forms of NS1: (i) the wing flexible loop, (ii) the outer, electrostatic surface of the wing, and (iii) the spaghetti loop face of the β-ladder. One additional MAb mapped to the distal tip of the β-ladder and conferred a lower level of protection against WNV despite not binding to NS1 on the surface of infected cells. Our study defines the epitopes and modes of binding of protective anti-NS1 MAb antibodies following WNV infection, which may inform the development of NS1-based countermeasures against flaviviruses. IMPORTANCE Therapeutic antibodies against flaviviruses often promote neutralization by targeting the envelope protein of the virion. However, this approach is hindered by a possible concern for antibody-dependent enhancement of infection and paradoxical worsening of disease. As an alternative strategy, antibodies targeting flavivirus nonstructural protein 1 (NS1), which is absent from the virion, can protect against disease and do not cause enhanced infection. Here, we evaluate the structure-function relationships and protective activity of West Nile virus (WNV) NS1-specific monoclonal antibodies (MAbs) isolated from the memory B cells of a naturally infected human donor. We identify several anti-NS1 MAbs that protect mice against lethal WNV challenge and map their epitopes using charge reversal mutagenesis. Antibodies targeting specific regions in the NS1 structure could serve as the basis for countermeasures that control WNV infection in humans.

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Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys.

Publications

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys.

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