title: HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates.
abstract: A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Petro
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Weinrick
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Khajoueinejad
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Burn
authors.affiliation: Histology and Comparative Pathology Facility, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Rani
authors.initials: R
authors.lastname: Sellers
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold