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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

ΔgD−/+gD−1-vaccinated cycling mice are protected against intravaginal HSV-2 challenge.C57BL/6 mice were treated (w/MPA) or not (w/o MPA) with medroxyprogesterone (MPA) 5 days previous to subcutaneous prime and boost 3 weeks apart either with HSV-2 ΔgD−/+gD−1 (ΔgD) or VD60 cell lysate (Control). 16 days after boost, all mice were treated with MPA and 5 days later challenged intravaginally with an LD90 of wild-type HSV-2(4674) (n = 5 mice per group). Statistical significance was measured by log-rank Mantel–Cox test; ***p < 0.001, treatments vs Control.DOI:http://dx.doi.org/10.7554/eLife.06054.006
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fig3s1: ΔgD−/+gD−1-vaccinated cycling mice are protected against intravaginal HSV-2 challenge.C57BL/6 mice were treated (w/MPA) or not (w/o MPA) with medroxyprogesterone (MPA) 5 days previous to subcutaneous prime and boost 3 weeks apart either with HSV-2 ΔgD−/+gD−1 (ΔgD) or VD60 cell lysate (Control). 16 days after boost, all mice were treated with MPA and 5 days later challenged intravaginally with an LD90 of wild-type HSV-2(4674) (n = 5 mice per group). Statistical significance was measured by log-rank Mantel–Cox test; ***p < 0.001, treatments vs Control.DOI:http://dx.doi.org/10.7554/eLife.06054.006

Mentions: Mice were pretreated with medroxyprogesterone (MPA) to hormonally synchronize them prior to immunization in the efficacy studies. However, MPA can modulate innate and adaptive immune responses (Kaushic et al., 2003; Vicetti Miguel et al., 2012). Therefore we conducted additional experiments with cycling and MPA treated mice. The vaccine protected 100% of mice independent of hormonal treatment (Figure 3—figure supplement 1). In addition, mouse strains can differ in susceptibility and immune responses to pathogens. Therefore we also tested the efficacy of the vaccine against HSV-2 intravaginal infection in BALB/c mice. Consistent with the findings in C57BL/6 mice, 100% of HSV-2 ΔgD−/+gD−1-vaccinated mice survived intravaginal challenge (Figure 3I) and no infectious virus or viral DNA was recovered from neural tissues at day 7 and 21 post-infection (Figure 3J).


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)

ΔgD−/+gD−1-vaccinated cycling mice are protected against intravaginal HSV-2 challenge.C57BL/6 mice were treated (w/MPA) or not (w/o MPA) with medroxyprogesterone (MPA) 5 days previous to subcutaneous prime and boost 3 weeks apart either with HSV-2 ΔgD−/+gD−1 (ΔgD) or VD60 cell lysate (Control). 16 days after boost, all mice were treated with MPA and 5 days later challenged intravaginally with an LD90 of wild-type HSV-2(4674) (n = 5 mice per group). Statistical significance was measured by log-rank Mantel–Cox test; ***p < 0.001, treatments vs Control.DOI:http://dx.doi.org/10.7554/eLife.06054.006
© Copyright Policy
Related In: Results  -  Collection

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

fig3s1: ΔgD−/+gD−1-vaccinated cycling mice are protected against intravaginal HSV-2 challenge.C57BL/6 mice were treated (w/MPA) or not (w/o MPA) with medroxyprogesterone (MPA) 5 days previous to subcutaneous prime and boost 3 weeks apart either with HSV-2 ΔgD−/+gD−1 (ΔgD) or VD60 cell lysate (Control). 16 days after boost, all mice were treated with MPA and 5 days later challenged intravaginally with an LD90 of wild-type HSV-2(4674) (n = 5 mice per group). Statistical significance was measured by log-rank Mantel–Cox test; ***p < 0.001, treatments vs Control.DOI:http://dx.doi.org/10.7554/eLife.06054.006
Mentions: Mice were pretreated with medroxyprogesterone (MPA) to hormonally synchronize them prior to immunization in the efficacy studies. However, MPA can modulate innate and adaptive immune responses (Kaushic et al., 2003; Vicetti Miguel et al., 2012). Therefore we conducted additional experiments with cycling and MPA treated mice. The vaccine protected 100% of mice independent of hormonal treatment (Figure 3—figure supplement 1). In addition, mouse strains can differ in susceptibility and immune responses to pathogens. Therefore we also tested the efficacy of the vaccine against HSV-2 intravaginal infection in BALB/c mice. Consistent with the findings in C57BL/6 mice, 100% of HSV-2 ΔgD−/+gD−1-vaccinated mice survived intravaginal challenge (Figure 3I) and no infectious virus or viral DNA was recovered from neural tissues at day 7 and 21 post-infection (Figure 3J).

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