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.
Highlights
Many herpes simplex virus 2 (HSV-2) vaccine candidates have been proposed, and most may be grouped into one of four classes: 1. adjuvanted HSV-2 proteins [1,2,3,4,5,6,7]; 2
117 naıve and immunized animals were analyzed to compare pre-challenge serum levels of pan-HSV-2 IgG to two measures of protection against HSV-2. In both mice and guinea pigs, we observed that increased prechallenge levels of pan-HSV-2 IgG quantitatively correlated with 1. reductions in HSV-2 challenge virus shedding and 2. increased survival frequency following a lethal HSV-2 challenge. These results suggest that serum levels of pan-HSV-2 IgG antibody may provide a simple and useful screening tool to aid in the identification of a HSV-2 vaccine that elicits robust protection against HSV-2 genital herpes
The current study demonstrates that in vaccinated mice and guinea pigs, the pan-HSV-2 IgG antibody response to several vaccines varies in proportion to protection against HSV-2
Summary
Many herpes simplex virus 2 (HSV-2) vaccine candidates have been proposed, and most may be grouped into one of four classes: 1. adjuvanted HSV-2 proteins [1,2,3,4,5,6,7]; 2. HSV-2 glycoprotein subunit vaccines have failed to protect humans from acquiring genital herpes in several clinical trials [32,33,34,35,36,37]. In the most recent of these phase III clinical trials, 3,798 women immunized with an adjuvanted gD-2 vaccine acquired HSV-2 genital herpes at the same rate as 3,076 placebo-treated controls [32,38]. These failures have raised concerns that a HSV-2 vaccine may not be tenable [38,39,40]. Several HSV-2 vaccines elicit greater protection than gD-2 vaccines in animal models [18,23,29,31], but have not been evaluated in clinical trials
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