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Abstract
Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.
Highlights
We used a high throughput biosensor assay to evaluate whether gD2-immunized guinea pigs produce antibodies that block the activities of gD2 epitopes involved in virus entry and cell-to-cell spread
We re-evaluated our prior report of epitope-specific antibody responses in the gD2 Herpevac Trial, a trial that failed to protect subjects against Herpes simplex virus type 2 (HSV-2) genital infection
We conclude that neutralizing antibodies and antibodies to multiple gD2 epitopes involved in virus entry and cell-to-cell spread represent important immune correlates of protection
Summary
One half-billion people worldwide are infected with herpes simplex virus type 2 (HSV2) and another one-quarter billion have genital infection caused by herpes simplex virus type 1 (HSV-1) [1, 2]. HSV-2 genital infection carries a three-fold increased risk for acquisition and transmission of HIV [7]. The Herpevac Trial for Women was the most recent large prophylactic genital herpes human vaccine trial that involved immunizing HSV-1 and HSV-2 doubly seronegative women with gD2 subunit antigen [10]. The vaccine protected against HSV-1 genital infection, but not HSV-2. Higher ELISA antibody titers were associated with reduced acquisition of HSV-1, highlighting the importance of antibodies for protection against genital herpes [10]. Vaccine-induced antibodies correlate with protection against other sexually transmitted infections, including human papilloma virus (HPV) and hepatitis B virus (HBV) [11]. Our strategy has focused on the generation of robust antibody responses for a prophylactic HSV-2 vaccine
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