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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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HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.(A) Survival of SCID mice inoculated with up to 107 pfu of HSV-2 ΔgD−/+gD−1 or up to 105 pfu of the parental HSV-2(G) strain either intravaginally (ivag) or subcutaneously (sc). Statistical significance was measured by log-rank Mantel–Cox test; **p < 0.01 for ΔgD and WT after ivag inoculation. (B) Epithelial and (C) Neurological disease scores for SCID mice inoculated with the different viruses at indicated doses. (D) HSV-2 DNA (qPCR, UL30 gene) in genital tract and neural tissue samples at day 5 post-virus inoculation. The Ct cut off was determined with HSV-uninfected naïve samples. Statistical significance was measured by two-way ANOVA with Sidak's multiple comparisons test for (B, C and D); ***p < 0.001. HSV-2 ΔgD−/+gD−1 and its parental strain are abbreviated as ΔgD and WT, respectively.DOI:http://dx.doi.org/10.7554/eLife.06054.004
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fig2: HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.(A) Survival of SCID mice inoculated with up to 107 pfu of HSV-2 ΔgD−/+gD−1 or up to 105 pfu of the parental HSV-2(G) strain either intravaginally (ivag) or subcutaneously (sc). Statistical significance was measured by log-rank Mantel–Cox test; **p < 0.01 for ΔgD and WT after ivag inoculation. (B) Epithelial and (C) Neurological disease scores for SCID mice inoculated with the different viruses at indicated doses. (D) HSV-2 DNA (qPCR, UL30 gene) in genital tract and neural tissue samples at day 5 post-virus inoculation. The Ct cut off was determined with HSV-uninfected naïve samples. Statistical significance was measured by two-way ANOVA with Sidak's multiple comparisons test for (B, C and D); ***p < 0.001. HSV-2 ΔgD−/+gD−1 and its parental strain are abbreviated as ΔgD and WT, respectively.DOI:http://dx.doi.org/10.7554/eLife.06054.004

Mentions: To assess whether HSV-2 ΔgD−/+gD−1 is safe in vivo, severe combined immunodeficiency (SCID) mice were inoculated subcutaneously or intravaginally with the complemented HSV-2 ΔgD−/+gD−1 strain or parental HSV-2(G) virus (Figure 2A). SCID mice inoculated intravaginally with 107 pfu of HSV-2 ΔgD−/+gD−1 manifested no signs of disease, whereas animals inoculated with 104 pfu of HSV-2(G) quickly succumbed to the infection and manifested severe HSV-2-induced epithelial and neurological disease (Figure 2B,C). Subcutaneous inoculation with wild-type virus also induced disease (60% mortality with 105 pfu), while no evidence of disease was observed following exposure to high doses of HSV-2 ΔgD−/+gD−1 in SCID mice. Moreover, no virus was detected in the neural tissue of SCID mice inoculated intravaginally with HSV-2 ΔgD−/+gD−1 by qPCR (Figure 2D).10.7554/eLife.06054.004Figure 2.HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.


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)

HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.(A) Survival of SCID mice inoculated with up to 107 pfu of HSV-2 ΔgD−/+gD−1 or up to 105 pfu of the parental HSV-2(G) strain either intravaginally (ivag) or subcutaneously (sc). Statistical significance was measured by log-rank Mantel–Cox test; **p < 0.01 for ΔgD and WT after ivag inoculation. (B) Epithelial and (C) Neurological disease scores for SCID mice inoculated with the different viruses at indicated doses. (D) HSV-2 DNA (qPCR, UL30 gene) in genital tract and neural tissue samples at day 5 post-virus inoculation. The Ct cut off was determined with HSV-uninfected naïve samples. Statistical significance was measured by two-way ANOVA with Sidak's multiple comparisons test for (B, C and D); ***p < 0.001. HSV-2 ΔgD−/+gD−1 and its parental strain are abbreviated as ΔgD and WT, respectively.DOI:http://dx.doi.org/10.7554/eLife.06054.004
© Copyright Policy
Related In: Results  -  Collection

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fig2: HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.(A) Survival of SCID mice inoculated with up to 107 pfu of HSV-2 ΔgD−/+gD−1 or up to 105 pfu of the parental HSV-2(G) strain either intravaginally (ivag) or subcutaneously (sc). Statistical significance was measured by log-rank Mantel–Cox test; **p < 0.01 for ΔgD and WT after ivag inoculation. (B) Epithelial and (C) Neurological disease scores for SCID mice inoculated with the different viruses at indicated doses. (D) HSV-2 DNA (qPCR, UL30 gene) in genital tract and neural tissue samples at day 5 post-virus inoculation. The Ct cut off was determined with HSV-uninfected naïve samples. Statistical significance was measured by two-way ANOVA with Sidak's multiple comparisons test for (B, C and D); ***p < 0.001. HSV-2 ΔgD−/+gD−1 and its parental strain are abbreviated as ΔgD and WT, respectively.DOI:http://dx.doi.org/10.7554/eLife.06054.004
Mentions: To assess whether HSV-2 ΔgD−/+gD−1 is safe in vivo, severe combined immunodeficiency (SCID) mice were inoculated subcutaneously or intravaginally with the complemented HSV-2 ΔgD−/+gD−1 strain or parental HSV-2(G) virus (Figure 2A). SCID mice inoculated intravaginally with 107 pfu of HSV-2 ΔgD−/+gD−1 manifested no signs of disease, whereas animals inoculated with 104 pfu of HSV-2(G) quickly succumbed to the infection and manifested severe HSV-2-induced epithelial and neurological disease (Figure 2B,C). Subcutaneous inoculation with wild-type virus also induced disease (60% mortality with 105 pfu), while no evidence of disease was observed following exposure to high doses of HSV-2 ΔgD−/+gD−1 in SCID mice. Moreover, no virus was detected in the neural tissue of SCID mice inoculated intravaginally with HSV-2 ΔgD−/+gD−1 by qPCR (Figure 2D).10.7554/eLife.06054.004Figure 2.HSV-2 ΔgD−/+gD−1 is attenuated in severe combined immunodeficiency (SCID) mice.

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