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HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates
Christopher D. Petro, … , William R. Jacobs Jr, Betsy C. Herold
Christopher D. Petro, … , William R. Jacobs Jr, Betsy C. Herold
Published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e88529. https://doi.org/10.1172/jci.insight.88529.
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Categories: Research Article Vaccines Virology

HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates

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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

Christopher D. Petro, Brian Weinrick, Nazanin Khajoueinejad, Clare Burn, Rani Sellers, William R. Jacobs Jr, Betsy C. Herold

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Figure 1

HSV-2ΔgD-2 provides complete protection following intravaginal or skin challenge with vaccine doses as low as 5 × 104 PFU.

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HSV-2ΔgD-2 provides complete protection following intravaginal or skin c...
C57BL/6 mice were primed and, 21 days later, were boosted s.c. with 5 × 104 PFU, 5 × 105 PFU, or 5 × 106 PFU of HSV-2 ΔgD-2 or VD60 lysates (control). Mice were subsequently challenged 21 days after boost with an LD90 of HSV-2(4674) either (A) intravaginally or (B) via skin scarification and followed for survival (n = 5 mice/group). (C) Serum was assessed for HSV-2 antibodies by ELISA before (PreBleed), day 7 after prime, and day 7 after boost; each symbol represents optical densitometry units (OD) for an individual mouse (n = 5/group); lines represent mean of each group. ΔgD-2– and control-vaccinated groups were compared for survival by Kaplan-Meier and for Ab responses by 2-way ANOVA; **P < 0.01, ***P < 0.001.
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