Better neutralization of herpes simplex virus type 1 (HSV-1) than HSV-2 by antibody from recipients of GlaxoSmithKline HSV-2 glycoprotein D2 subunit vaccine

Abstract

The Herpevac Trial evaluated a herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 infection but not genital HSV-2 infection. We evaluated sera from 30 women seronegative for HSV-1 and HSV-2 who were immunized with gD2 in the Herpevac Trial. Neutralizing antibody titers to HSV-1 were 3.5-fold higher than those to HSV-2 (P < .001). HSV-2 gC2 and gE2 on the virus blocked neutralization by gD2 antibody, while HSV-1 gC1 and gE1 did not block neutralization by gD2 antibody. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results, and shielding neutralizing domains provides a potential mechanism.

Keywords: HSV-1; HSV-2; Herpevac Trial; glycoprotein C; glycoprotein D; glycoprotein E; neutralizing antibody; vaccine.

Figure 1.

A, Fifty percent end point neutralizing antibody titers of herpes simplex virus type 1 (HSV-1) and HSV-2 Herpevac Trial sera obtained at months 0 and 7 from hepatitis A (HepA; n = 5) and glycoprotein D2 (gD2; n = 30) immunized subjects. B, Neutralization at each serum dilution of gD2-immunized subjects (n = 30). The dotted line represents 50% neutralization. The solid lines represent the mean percentage neutralization at each dilution. The curves were compared by 2-way analysis of variance and the Bonferroni test for repeated measures. The values at each point are significantly different, except for 1:640. C, Correlation of gD2 enzyme-linked immunosorbent assay (ELISA) titers with HSV-1 (P < .001) or HSV-2 (P < .001) neutralizing antibody titers of subjects immunized with gD2 (n = 30). P values were calculated using the Pearson correlation for nonparametric data and a 2-tailed analysis. D, Fifty percent end point neutralizing antibody titers to HSV-1 or HSV-2 by sera obtained between 1995 and 1997 at month 7 from placebo recipient (n = 3) or gD2-immunized subjects (n = 10; 4 from HSV-007 and 6 from HSV-014 and 015). E, The same 6 HSV-014 and 015 sera were tested against 3 low-passage HSV-1 strains and 2 low-passage HSV-2 strains (each strain represented by a different color). Note that the y-axis scale differs in panel E. P values for panels A and D were calculated by 1-way analysis of variance, using the Dunn multiple comparisons test, whereas the P value in panel E was calculated by the Mann–Whitney test. In panels A, D, and E, data are geometric mean titers with 95% confidence intervals.

Figure 2.

A, Log₁₀ neutralization of wild-type (WT), gCnull, and gEnull mutant viruses by sera from gD2 HSV-014 and 015 vaccinees (n = 6). Error bars represent standard errors of the mean. B, Enzyme-linked immunosorbent assay (ELISA) titers at a 1:500 dilution of vaccine sera (n = 6). The dotted line shows the ELISA value of serum specimens seronegative for both herpes simplex virus type 1 (HSV-1) and HSV-2. Results represent geometric mean titers with 95% confidence intervals. P values in panels A and B were calculated by 1-way analysis of variance with Tukey posttest analysis for pair-wise comparison. C, HSV-1 glycoprotein C1 (gC1) and gE1 fail to block antibody access to gD1. D, HSV-2 gC2 and gE2 shield antibody access to gD2. Abbreviation: NS, not significant.