Abstract
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus that is highly prevalent worldwide, causing a range of symptoms that result in significant healthcare costs and human suffering. ACAM529 is a replication-defective vaccine candidate prepared by growing the previously described dl5-29 on a cell line appropriate for GMP manufacturing. This vaccine, when administered subcutaneously, was previously shown to protect mice from a lethal vaginal HSV-2 challenge and to afford better protection than adjuvanted glycoprotein D (gD) in guinea pigs. Here we show that ACAM529 given via the intramuscular route affords significantly greater immunogenicity and protection in comparison with subcutaneous administration in the mouse vaginal HSV-2 challenge model. Further, we describe a side-by-side comparison of intramuscular ACAM529 with a gD vaccine across a range of challenge virus doses. While differences in protection against death are not significant, ACAM529 protects significantly better against mucosal infection, reducing peak challenge virus shedding at the highest challenge dose by over 500-fold versus 5-fold for gD. Over 27% (11/40) of ACAM529-immunized animals were protected from viral shedding while 2.5% (1/40) were protected by the gD vaccine. Similarly, 35% (7/20) of mice vaccinated with ACAM529 were protected from infection of their dorsal root ganglia while none of the gD-vaccinated mice were protected. These results indicate that measuring infection of the vaginal mucosa and of dorsal root ganglia over a range of challenge doses is more sensitive than evaluating survival at a single challenge dose as a means of directly comparing vaccine efficacy in the mouse vaginal challenge model. The data also support further investigation of ACAM529 for prophylaxis in human subjects.
Highlights
herpes simplex virus type 2 (HSV-2) is a global health problem, causing clinical manifestations ranging from mild skin or mucosal ulcers to lethal disseminated infections in newborns [1,2]
A subunit vaccine made using recombinant glycoprotein D of HSV-2 strain G was shown to be well tolerated and immunogenic [6], and to achieve a disease reduction of 73% (P = 0.01) and a trend for reduction in infections of about 43% (P = 0.08) in women who were HSV-1 seronegative [7]; a larger clinical trial with a different target population failed to demonstrate efficacy against HSV-2 and significantly increased shedding frequency in vaccine recipients who became infected with HSV-2 [8]
An alternative approach is the replication-defective virus dl5-29 which was constructed by deleting the UL5 and UL29 genes of herpes simplex virus type 2 (HSV-2) [18]
Summary
HSV-2 is a global health problem, causing clinical manifestations ranging from mild skin or mucosal ulcers to lethal disseminated infections in newborns [1,2]. In an effort to address the medical and societal burden caused by HSV-2, a number of vaccines have been evaluated in the clinic over the past decades [5]. When administered to mice or guinea pigs subcutaneously, dl induces robust protective immune responses in vivo, and yet does not replicate or establish latency [19,20,21]. These data suggest that dl could be an effective vaccine for human use to prevent HSV-2 infections and genital herpes disease. In preparation for evaluation in a clinical setting, a new production cell line and virus master seed were prepared and the resulting vaccine was renamed ACAM529
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