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Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2.

Halford WP, Geltz J, Gershburg E - PLoS ONE (2013)

Bottom Line: These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ∼500-fold range.For 5 of the 6 immunogens tested, pre-challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge.Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America. halford@siumed.edu

ABSTRACT
We lack a correlate of immunity to herpes simplex virus 2 (HSV-2) that may be used to differentiate whether a HSV-2 vaccine elicits robust or anemic protection against genital herpes. This gap in knowledge is often attributed to a failure to measure the correct component of the adaptive immune response to HSV-2. However, efforts to identify a correlate of immunity have focused on subunit vaccines that contain less than 3% of HSV-2's 40,000-amino-acid proteome. We were interested to determine if a correlate of immunity might be more readily identified if 1. animals were immunized with a polyvalent immunogen such as a live virus and/or 2. the magnitude of the vaccine-induced immune response was gauged in terms of the IgG antibody response to all of HSV-2's antigens (pan-HSV-2 IgG). Pre-challenge pan-HSV-2 IgG levels and protection against HSV-2 were compared in mice and/or guinea pigs immunized with a gD-2 subunit vaccine, wild-type HSV-2, or one of several attenuated HSV-2 ICP0 (-) viruses (0Δ254, 0Δ810, 0ΔRING, or 0ΔNLS). These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ∼500-fold range. For 5 of the 6 immunogens tested, pre-challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge. Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.

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Pan-HSV-2 IgG levels correlate with protection against ocular HSV-2 challenge in mice.(A) Design of vaccine-ocular HSV-2 challenge experiment in mice. Mice were initially inoculated in their right eye on Day 0 with culture medium or 105 pfu per eye of one of the five indicated viruses (n = 8 per group). Mice inoculated with HSV-2 MS were treated with acyclovir from Days 0 to 20 post-immunization to restrict viral pathogenesis. On Day 60, blood was harvested, and on Day 70, mice were challenged in the left eye with 105 pfu of wild-type HSV-2 MS. (B) Mean ± sem pan-HSV-2 IgG levels in pre-challenge serum, as determined by a flow cytometry-based assay. (C) For each mouse (one symbol per mouse), the average amount of infectious HSV-2 shed on Days 1, 2, and 3-post ocular challenge (y-axis) was plotted as a function of the pre-challenge HSV-2 IgG levels observed in the same mouse (x-axis). The solid black line represents the best-fit linear regression model, y = 3.35–0.56x, for the 48 matched datum pairs. (D) Mean ± sem of log (pan-HSV-2 IgG) in each immunization group is plotted on the x-axis versus mean ± sem ocular HSV-2 shedding on the y-axis. The solid black line represents the best-fit linear regression model, y = 3.44–0.64x, for these 6 matched averages (r2 = 0.86). Groups of immunized mice that exhibited a significant reduction in ocular HSV-2 shedding relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.001), as determined by one-way ANOVA and Tukey's post-hoc t-test. (E) Survival frequency in each group is plotted as a function of the mean ± sem pan-HSV-2 IgG antibody level observed in each group. Groups of immunized mice that exhibited a significant difference in survival frequency relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.0001), as determined by Fisher's Exact Test.
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pone-0065523-g002: Pan-HSV-2 IgG levels correlate with protection against ocular HSV-2 challenge in mice.(A) Design of vaccine-ocular HSV-2 challenge experiment in mice. Mice were initially inoculated in their right eye on Day 0 with culture medium or 105 pfu per eye of one of the five indicated viruses (n = 8 per group). Mice inoculated with HSV-2 MS were treated with acyclovir from Days 0 to 20 post-immunization to restrict viral pathogenesis. On Day 60, blood was harvested, and on Day 70, mice were challenged in the left eye with 105 pfu of wild-type HSV-2 MS. (B) Mean ± sem pan-HSV-2 IgG levels in pre-challenge serum, as determined by a flow cytometry-based assay. (C) For each mouse (one symbol per mouse), the average amount of infectious HSV-2 shed on Days 1, 2, and 3-post ocular challenge (y-axis) was plotted as a function of the pre-challenge HSV-2 IgG levels observed in the same mouse (x-axis). The solid black line represents the best-fit linear regression model, y = 3.35–0.56x, for the 48 matched datum pairs. (D) Mean ± sem of log (pan-HSV-2 IgG) in each immunization group is plotted on the x-axis versus mean ± sem ocular HSV-2 shedding on the y-axis. The solid black line represents the best-fit linear regression model, y = 3.44–0.64x, for these 6 matched averages (r2 = 0.86). Groups of immunized mice that exhibited a significant reduction in ocular HSV-2 shedding relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.001), as determined by one-way ANOVA and Tukey's post-hoc t-test. (E) Survival frequency in each group is plotted as a function of the mean ± sem pan-HSV-2 IgG antibody level observed in each group. Groups of immunized mice that exhibited a significant difference in survival frequency relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.0001), as determined by Fisher's Exact Test.

Mentions: The design of the original experiment is reviewed. Five of 6 groups of mice were inoculated in the right eye with culture medium (naïve controls) or 100,000 pfu per right eye of the HSV-2 ICP0− mutant viruses HSV-2 0ΔNLS, 0Δ810, 0Δ254, or 0ΔRING (Fig. 2A). A sixth group was similarly inoculated with wild-type HSV-2 MS, but the pathogenesis of infection was restrained by treating mice with acyclovir (Fig. 2A). Blood was drawn on Day 60, and mice were challenged on Day 70 with 100,000 pfu per left eye of HSV-2 MS (Fig. 2A). The left eyes of these mice were swabbed daily between Days 1 and 3 post-challenge to monitor viral replication, and disease onset was observed over a 30 day-period (Fig. 2A).


Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2.

Halford WP, Geltz J, Gershburg E - PLoS ONE (2013)

Pan-HSV-2 IgG levels correlate with protection against ocular HSV-2 challenge in mice.(A) Design of vaccine-ocular HSV-2 challenge experiment in mice. Mice were initially inoculated in their right eye on Day 0 with culture medium or 105 pfu per eye of one of the five indicated viruses (n = 8 per group). Mice inoculated with HSV-2 MS were treated with acyclovir from Days 0 to 20 post-immunization to restrict viral pathogenesis. On Day 60, blood was harvested, and on Day 70, mice were challenged in the left eye with 105 pfu of wild-type HSV-2 MS. (B) Mean ± sem pan-HSV-2 IgG levels in pre-challenge serum, as determined by a flow cytometry-based assay. (C) For each mouse (one symbol per mouse), the average amount of infectious HSV-2 shed on Days 1, 2, and 3-post ocular challenge (y-axis) was plotted as a function of the pre-challenge HSV-2 IgG levels observed in the same mouse (x-axis). The solid black line represents the best-fit linear regression model, y = 3.35–0.56x, for the 48 matched datum pairs. (D) Mean ± sem of log (pan-HSV-2 IgG) in each immunization group is plotted on the x-axis versus mean ± sem ocular HSV-2 shedding on the y-axis. The solid black line represents the best-fit linear regression model, y = 3.44–0.64x, for these 6 matched averages (r2 = 0.86). Groups of immunized mice that exhibited a significant reduction in ocular HSV-2 shedding relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.001), as determined by one-way ANOVA and Tukey's post-hoc t-test. (E) Survival frequency in each group is plotted as a function of the mean ± sem pan-HSV-2 IgG antibody level observed in each group. Groups of immunized mice that exhibited a significant difference in survival frequency relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.0001), as determined by Fisher's Exact Test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675040&req=5

pone-0065523-g002: Pan-HSV-2 IgG levels correlate with protection against ocular HSV-2 challenge in mice.(A) Design of vaccine-ocular HSV-2 challenge experiment in mice. Mice were initially inoculated in their right eye on Day 0 with culture medium or 105 pfu per eye of one of the five indicated viruses (n = 8 per group). Mice inoculated with HSV-2 MS were treated with acyclovir from Days 0 to 20 post-immunization to restrict viral pathogenesis. On Day 60, blood was harvested, and on Day 70, mice were challenged in the left eye with 105 pfu of wild-type HSV-2 MS. (B) Mean ± sem pan-HSV-2 IgG levels in pre-challenge serum, as determined by a flow cytometry-based assay. (C) For each mouse (one symbol per mouse), the average amount of infectious HSV-2 shed on Days 1, 2, and 3-post ocular challenge (y-axis) was plotted as a function of the pre-challenge HSV-2 IgG levels observed in the same mouse (x-axis). The solid black line represents the best-fit linear regression model, y = 3.35–0.56x, for the 48 matched datum pairs. (D) Mean ± sem of log (pan-HSV-2 IgG) in each immunization group is plotted on the x-axis versus mean ± sem ocular HSV-2 shedding on the y-axis. The solid black line represents the best-fit linear regression model, y = 3.44–0.64x, for these 6 matched averages (r2 = 0.86). Groups of immunized mice that exhibited a significant reduction in ocular HSV-2 shedding relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.001), as determined by one-way ANOVA and Tukey's post-hoc t-test. (E) Survival frequency in each group is plotted as a function of the mean ± sem pan-HSV-2 IgG antibody level observed in each group. Groups of immunized mice that exhibited a significant difference in survival frequency relative to naïve mice are indicated by a single asterisk (*; p<0.05) or double-asterisk (**; p<0.0001), as determined by Fisher's Exact Test.
Mentions: The design of the original experiment is reviewed. Five of 6 groups of mice were inoculated in the right eye with culture medium (naïve controls) or 100,000 pfu per right eye of the HSV-2 ICP0− mutant viruses HSV-2 0ΔNLS, 0Δ810, 0Δ254, or 0ΔRING (Fig. 2A). A sixth group was similarly inoculated with wild-type HSV-2 MS, but the pathogenesis of infection was restrained by treating mice with acyclovir (Fig. 2A). Blood was drawn on Day 60, and mice were challenged on Day 70 with 100,000 pfu per left eye of HSV-2 MS (Fig. 2A). The left eyes of these mice were swabbed daily between Days 1 and 3 post-challenge to monitor viral replication, and disease onset was observed over a 30 day-period (Fig. 2A).

Bottom Line: These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ∼500-fold range.For 5 of the 6 immunogens tested, pre-challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge.Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America. halford@siumed.edu

ABSTRACT
We lack a correlate of immunity to herpes simplex virus 2 (HSV-2) that may be used to differentiate whether a HSV-2 vaccine elicits robust or anemic protection against genital herpes. This gap in knowledge is often attributed to a failure to measure the correct component of the adaptive immune response to HSV-2. However, efforts to identify a correlate of immunity have focused on subunit vaccines that contain less than 3% of HSV-2's 40,000-amino-acid proteome. We were interested to determine if a correlate of immunity might be more readily identified if 1. animals were immunized with a polyvalent immunogen such as a live virus and/or 2. the magnitude of the vaccine-induced immune response was gauged in terms of the IgG antibody response to all of HSV-2's antigens (pan-HSV-2 IgG). Pre-challenge pan-HSV-2 IgG levels and protection against HSV-2 were compared in mice and/or guinea pigs immunized with a gD-2 subunit vaccine, wild-type HSV-2, or one of several attenuated HSV-2 ICP0 (-) viruses (0Δ254, 0Δ810, 0ΔRING, or 0ΔNLS). These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ∼500-fold range. For 5 of the 6 immunogens tested, pre-challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge. Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.

Show MeSH
Related in: MedlinePlus