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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.

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Related in: MedlinePlus

Antibody-mediated protection requires FcγR and FcRn expression.Epithelial and neurological disease scores in (A, B) FcγR−/− and (C, D) FcRn−/− mice receiving serum from control- or HSV-2 ΔgD−/+gD−1-vaccinated wild-type mice and then challenged intravaginally with HSV-2(4674) (n = 5 mice per group).DOI:http://dx.doi.org/10.7554/eLife.06054.014
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fig7s1: Antibody-mediated protection requires FcγR and FcRn expression.Epithelial and neurological disease scores in (A, B) FcγR−/− and (C, D) FcRn−/− mice receiving serum from control- or HSV-2 ΔgD−/+gD−1-vaccinated wild-type mice and then challenged intravaginally with HSV-2(4674) (n = 5 mice per group).DOI:http://dx.doi.org/10.7554/eLife.06054.014

Mentions: Importantly, antibody-mediated protection was lost when serum was transferred to FcγR and FcRn knock-out mice (Figure 7A,B and Figure 7—figure supplement 1A,B). HSV-specific Abs were detected in vaginal washes of the FcγR−/− mice, but failed to provide protection, whereas Abs were not detected in vaginal washes from FcRn−/− mice consistent with the role of FcRn in transport of Abs from serum to the mucosa (Li et al., 2011) (Figure 7C,D).10.7554/eLife.06054.013Figure 7.Antibody-mediated protection requires FcγR and FcRn expression.


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)

Antibody-mediated protection requires FcγR and FcRn expression.Epithelial and neurological disease scores in (A, B) FcγR−/− and (C, D) FcRn−/− mice receiving serum from control- or HSV-2 ΔgD−/+gD−1-vaccinated wild-type mice and then challenged intravaginally with HSV-2(4674) (n = 5 mice per group).DOI:http://dx.doi.org/10.7554/eLife.06054.014
© Copyright Policy
Related In: Results  -  Collection

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

fig7s1: Antibody-mediated protection requires FcγR and FcRn expression.Epithelial and neurological disease scores in (A, B) FcγR−/− and (C, D) FcRn−/− mice receiving serum from control- or HSV-2 ΔgD−/+gD−1-vaccinated wild-type mice and then challenged intravaginally with HSV-2(4674) (n = 5 mice per group).DOI:http://dx.doi.org/10.7554/eLife.06054.014
Mentions: Importantly, antibody-mediated protection was lost when serum was transferred to FcγR and FcRn knock-out mice (Figure 7A,B and Figure 7—figure supplement 1A,B). HSV-specific Abs were detected in vaginal washes of the FcγR−/− mice, but failed to provide protection, whereas Abs were not detected in vaginal washes from FcRn−/− mice consistent with the role of FcRn in transport of Abs from serum to the mucosa (Li et al., 2011) (Figure 7C,D).10.7554/eLife.06054.013Figure 7.Antibody-mediated protection requires FcγR and FcRn expression.

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