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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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Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-1 in a skin scarification model.Mice were subcutaneously primed and boosted 3 weeks apart either with HSV-2 ΔgD−/+gD−1 or Control VD60 cell lysate. 3 weeks later, mice were depilated and challenged in the flank skin with1 × 107 pfu HSV-1(17). Skin disease scores shown for challenged mice at days 3–11. Viral titers from biopsies of skin obtained on day 7–8 (Control mice) and day 14 (HSV-2 ΔgD−/+gD−1-vaccinated mice) (n = 5 mice per group, lines indicate means). Statistical significance was measured by unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.06054.008
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fig4s1: Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-1 in a skin scarification model.Mice were subcutaneously primed and boosted 3 weeks apart either with HSV-2 ΔgD−/+gD−1 or Control VD60 cell lysate. 3 weeks later, mice were depilated and challenged in the flank skin with1 × 107 pfu HSV-1(17). Skin disease scores shown for challenged mice at days 3–11. Viral titers from biopsies of skin obtained on day 7–8 (Control mice) and day 14 (HSV-2 ΔgD−/+gD−1-vaccinated mice) (n = 5 mice per group, lines indicate means). Statistical significance was measured by unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.06054.008

Mentions: The majority of clinical HSV lesions are observed on the external genital skin rather than cervicovaginal sites. Therefore, we tested the vaccine for efficacy in a modified skin scarification model against both serotypes. The flank skin of C57BL/6 mice was depilated and scarified prior to direct inoculation of the skin with 5 × 104 pfu (HSV-2(4674)) or 1 × 107 pfu (HSV-1(17)) in 5 µl volume. The control-vaccinated (VD60 lysate) mice developed zosteriform lesions, neurologic disease and succumbed to infection following challenge with HSV-2, whereas HSV-1 produced more modest signs (Figure 4A,B and Figure 4—figure supplement 1). More importantly, the HSV-2 ΔgD−/+gD−1-vaccinated mice showed minimal signs of epithelial disease (maximal disease score 1), no neurological signs and 100% survival after challenge with either serotype (Figure 4C and Figure 4—figure supplement 1). No HSV was detected by titering or qPCR in day 14 skin biopsies or neural tissue from HSV-2 ΔgD−/+gD−1-vaccinated mice; whereas virus was detected in 100% of control mice challenged with HSV-2 (Figure 4D,E).10.7554/eLife.06054.007Figure 4.Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-2 and HSV-1 in a skin scarification model.


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)

Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-1 in a skin scarification model.Mice were subcutaneously primed and boosted 3 weeks apart either with HSV-2 ΔgD−/+gD−1 or Control VD60 cell lysate. 3 weeks later, mice were depilated and challenged in the flank skin with1 × 107 pfu HSV-1(17). Skin disease scores shown for challenged mice at days 3–11. Viral titers from biopsies of skin obtained on day 7–8 (Control mice) and day 14 (HSV-2 ΔgD−/+gD−1-vaccinated mice) (n = 5 mice per group, lines indicate means). Statistical significance was measured by unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.06054.008
© Copyright Policy
Related In: Results  -  Collection

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

fig4s1: Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-1 in a skin scarification model.Mice were subcutaneously primed and boosted 3 weeks apart either with HSV-2 ΔgD−/+gD−1 or Control VD60 cell lysate. 3 weeks later, mice were depilated and challenged in the flank skin with1 × 107 pfu HSV-1(17). Skin disease scores shown for challenged mice at days 3–11. Viral titers from biopsies of skin obtained on day 7–8 (Control mice) and day 14 (HSV-2 ΔgD−/+gD−1-vaccinated mice) (n = 5 mice per group, lines indicate means). Statistical significance was measured by unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.06054.008
Mentions: The majority of clinical HSV lesions are observed on the external genital skin rather than cervicovaginal sites. Therefore, we tested the vaccine for efficacy in a modified skin scarification model against both serotypes. The flank skin of C57BL/6 mice was depilated and scarified prior to direct inoculation of the skin with 5 × 104 pfu (HSV-2(4674)) or 1 × 107 pfu (HSV-1(17)) in 5 µl volume. The control-vaccinated (VD60 lysate) mice developed zosteriform lesions, neurologic disease and succumbed to infection following challenge with HSV-2, whereas HSV-1 produced more modest signs (Figure 4A,B and Figure 4—figure supplement 1). More importantly, the HSV-2 ΔgD−/+gD−1-vaccinated mice showed minimal signs of epithelial disease (maximal disease score 1), no neurological signs and 100% survival after challenge with either serotype (Figure 4C and Figure 4—figure supplement 1). No HSV was detected by titering or qPCR in day 14 skin biopsies or neural tissue from HSV-2 ΔgD−/+gD−1-vaccinated mice; whereas virus was detected in 100% of control mice challenged with HSV-2 (Figure 4D,E).10.7554/eLife.06054.007Figure 4.Vaccination with HSV-2 ΔgD−/+gD−1 protects mice infected with HSV-2 and HSV-1 in a skin scarification model.

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