HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates
Christopher D. Petro, Brian Weinrick, Nazanin Khajoueinejad, Clare Burn, Rani Sellers, William R. Jacobs Jr, Betsy C. Herold
Christopher D. Petro, Brian Weinrick, Nazanin Khajoueinejad, Clare Burn, Rani Sellers, William R. Jacobs Jr, Betsy C. Herold
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Research Article Vaccines Virology

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

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

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Figure 6

HSV-2 ΔgD-2 elicits cross-reactive HSV-specific FcγR effector antibodies.

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HSV-2 ΔgD-2 elicits cross-reactive HSV-specific FcγR effector antibodies...
Mice were vaccinated with ΔgD-2 or VD60 lysates (control) and subsequently challenged with HSV-2(4674) on the skin (n = 5/group). (A) Antibody-dependent cellular phagocytosis (ADCP) activity of serum from control or HSV-2 ΔgD-2–vaccinated mice 7 days after boost was quantified using THP-1 monocytic cell line and beads coated with HSV-2–infected cell lysates (v) or uninfected cell lysates (c) (left panel). The %ADCP is calculated as percent of cells positive for beads multiplied by the MFI of positive cells divided by 1 × 106. IFN-γ levels were measured in the supernatants 8 hours after incubation of THP-1 cells with the beads (right panel) (n = 4/group, line represents the mean). (B) Serum from 7 days postboost or 7 days postchallenge ΔgD-2– or control-immunized mice were further assessed for mFcγRIV (left panel) and mFcγRIII (right panel) activation via a luciferase effector cell reporter assay using HSV-2(4674)–infected target cells (data represented as mean ±SD values of 5 mice/group). (C) ΔgD-2 boost serum was pooled day 7 after boost and was assessed for mFcγRIV activation against cells infected with 5 different clinical isolates (n = 5 mice/pool; data represented as mean, SD obtained from replicates). (D) Day 7 postboost serum from mice vaccinated with ΔgD-2, UVΔgD-2, HIΔgD-2, or VD60 lysates (control) were evaluated for anti-HSV antibodies by ELISA using an HSV-2–infected cell lysate (data represented as mean ±SD values of 5 mice/group) and (E) mFcγRIV activation against HSV-2(4674)–infected cells (lines represent means). Dashed lines represent values from mock-infected mouse serum. For A and E, *P < 0.05, **P < 0.01, ***P < 0.001, ΔgD-2 vaccinated groups vs. control-vaccinated group via 2-way ANOVA. For B, C, and D, *P < 0.05, **P < 0.01, ***P < 0.001; AUCs were generated for each group and then analyzed via one-way ANOVA comparing ΔgD-2, UVΔgD-2, or HIΔgD-2 groups with control values (B and D) or against each other (C).