Limits...
Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Petro C, González PA, Cheshenko N, Jandl T, Khajoueinejad N, Bénard A, Sengupta M, Herold BC, Jacobs WR - Elife (2015)

Bottom Line: Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies.The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity.These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States.

ABSTRACT
Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

Show MeSH

Related in: MedlinePlus

Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against epithelial and neurological disease after HSV-2 intravaginal and skin challenge.Serum from Control- (VD60 cell lysate), ΔgD−/+gD−1-vaccinated mice, or ΔgD−/+gD−1 serum depleted of immunoglobulins using a Protein L column was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were challenged intravaginally with LD90 of HSV-2(4674) and followed for (A) epithelial and (B) neurological disease (n = 5 mice per group). (C) Serum from Control- or HSV-2 ΔgD−/+gD−1-vaccinated mice was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were depilated and challenged in the flank skin with HSV-2(4674) and followed for epithelial disease.DOI:http://dx.doi.org/10.7554/eLife.06054.010
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4352706&req=5

fig5s1: Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against epithelial and neurological disease after HSV-2 intravaginal and skin challenge.Serum from Control- (VD60 cell lysate), ΔgD−/+gD−1-vaccinated mice, or ΔgD−/+gD−1 serum depleted of immunoglobulins using a Protein L column was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were challenged intravaginally with LD90 of HSV-2(4674) and followed for (A) epithelial and (B) neurological disease (n = 5 mice per group). (C) Serum from Control- or HSV-2 ΔgD−/+gD−1-vaccinated mice was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were depilated and challenged in the flank skin with HSV-2(4674) and followed for epithelial disease.DOI:http://dx.doi.org/10.7554/eLife.06054.010

Mentions: To determine if protection could be transferred to naïve mice, 250 μl of serum (containing 750 μg of immunoglobulin administered intraperitoneally) or 3 × 106 T cells (administered intravenously) isolated from the blood or spleen and lymph nodes of immunized mice, respectively, were administered to C57BL/6 mice. 48 hr later, the mice were challenged with 105 pfu of HSV-2(4674) intravaginally. Mice treated with a single dose of immune serum displayed modest epithelial signs (mean score 2), but no neurologic disease with 100% survival (Figure 5A and Figure 5—figure supplement 1A,B). In contrast, mice that received T cells from immune mice or serum or T cells from the controls succumbed to disease. Depletion of immunoglobulins from the immune serum by passage on a Protein L column abolished the protective capacity. HSV-specific Abs were detected in vaginal washes in mice that received the immune, but not control serum (Figure 5B).10.7554/eLife.06054.009Figure 5.Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against HSV-2 intravaginal and skin challenge.


Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Petro C, González PA, Cheshenko N, Jandl T, Khajoueinejad N, Bénard A, Sengupta M, Herold BC, Jacobs WR - Elife (2015)

Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against epithelial and neurological disease after HSV-2 intravaginal and skin challenge.Serum from Control- (VD60 cell lysate), ΔgD−/+gD−1-vaccinated mice, or ΔgD−/+gD−1 serum depleted of immunoglobulins using a Protein L column was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were challenged intravaginally with LD90 of HSV-2(4674) and followed for (A) epithelial and (B) neurological disease (n = 5 mice per group). (C) Serum from Control- or HSV-2 ΔgD−/+gD−1-vaccinated mice was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were depilated and challenged in the flank skin with HSV-2(4674) and followed for epithelial disease.DOI:http://dx.doi.org/10.7554/eLife.06054.010
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352706&req=5

fig5s1: Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against epithelial and neurological disease after HSV-2 intravaginal and skin challenge.Serum from Control- (VD60 cell lysate), ΔgD−/+gD−1-vaccinated mice, or ΔgD−/+gD−1 serum depleted of immunoglobulins using a Protein L column was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were challenged intravaginally with LD90 of HSV-2(4674) and followed for (A) epithelial and (B) neurological disease (n = 5 mice per group). (C) Serum from Control- or HSV-2 ΔgD−/+gD−1-vaccinated mice was transferred intraperitoneally into naïve wild-type C57BL/6 mice. 24 hr later, mice were depilated and challenged in the flank skin with HSV-2(4674) and followed for epithelial disease.DOI:http://dx.doi.org/10.7554/eLife.06054.010
Mentions: To determine if protection could be transferred to naïve mice, 250 μl of serum (containing 750 μg of immunoglobulin administered intraperitoneally) or 3 × 106 T cells (administered intravenously) isolated from the blood or spleen and lymph nodes of immunized mice, respectively, were administered to C57BL/6 mice. 48 hr later, the mice were challenged with 105 pfu of HSV-2(4674) intravaginally. Mice treated with a single dose of immune serum displayed modest epithelial signs (mean score 2), but no neurologic disease with 100% survival (Figure 5A and Figure 5—figure supplement 1A,B). In contrast, mice that received T cells from immune mice or serum or T cells from the controls succumbed to disease. Depletion of immunoglobulins from the immune serum by passage on a Protein L column abolished the protective capacity. HSV-specific Abs were detected in vaginal washes in mice that received the immune, but not control serum (Figure 5B).10.7554/eLife.06054.009Figure 5.Serum from HSV-2 ΔgD−/+gD−1-vaccinated mice protects naïve mice against HSV-2 intravaginal and skin challenge.

Bottom Line: Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies.The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity.These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States.

ABSTRACT
Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

Show MeSH
Related in: MedlinePlus