Passive Infusion of Potently Neutralizing Hyperimmune Globulin Can Protect Against Cytomegalovirus Congenital Infection in a Rhesus Monkey Model
Year: 2016
Type: article
Abstract: Background. Cytomegalovirus (CMV) is the most common congenital infection worldwide, and a significant cause of infant hearing loss, brain damage, and neurodevelopmental delay. One potential therapeutic intervention to eliminate this disease is a maternal vaccine that blocks placental CMV transmission. Previously, we demonstrated a role for maternal CMV-neutralizing antibodies in protection against congenital CMV using a rhesus monkey model. In our model, CD4+ T-cell depleted dams with delayed neutralizing antibody responses experienced high rates of placental transmission (100%) and fetal loss (75%) shortly after rhesus CMV (rhCMV) challenge. Methods. To further investigate the protection conferred by maternal CMV-neutralizing antibodies, 6 rhCMV-seronegative rhesus macaque dams in the second trimester of pregnancy were CD4+ depleted. One week later, 3 dams were administered a single dose (100 mg/kg) of hyperimmune globulin (HIG) with a low neutralizing potency (IC50 = 22.64 µg/mL) 1 hour before intravenous (IV) challenge with a mixture of fibroblast-adapted (180.92) and epithelial-tropic (UCD52/UCD59) rhCMV strains. The remaining 3 dams received 2 doses (125 + 100 mg/kg) of a potently neutralizing HIG product (IC50 = 5.88 µg/mL) at 1 hour before IV rhCMV inoculation and 3 days postinfection, respectively. Results. Passive infusion of HIG before IV rhCMV challenge of CD4+-depleted dams provided complete protection against fetal loss (0 of 6 dams aborted; P < .01). Furthermore, 2 doses of the highly neutralizing HIG product achieved protection from placental transmission of rhCMV (0 of 3 transmitted), whereas a single dose of low-potency HIG product did not (2 of 3 dams transmitted). Peak plasma viral load was decreased in all HIG treated animals. Furthermore, targeted deep sequencing of rhCMV glycoprotein L and glycoprotein B from maternal plasma revealed that infused HIG created a genetic bottleneck, decreasing the diversity of viral haplotypes at both loci. Conclusion. Our data suggest that the presence of highly neutralizing antibodies at the time of rhCMV acquisition can prevent congenital infection, perhaps by influencing early viral replication. A better understanding of how antibody-mediated selection impacts placental rhCMV transmission and fetal outcome will inform future vaccine development efforts. Disclosures. All authors: No reported disclosures.
Source: Open Forum Infectious Diseases
Institutions: Duke University, Tulane University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,053
OpenAlex ID: W2559627068