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uncommon in the immune-competent host, and that HSV-1 antibodies reduce both the probability and the clinical symptoms of primary HSV-2 infection. Similarly, fetal transmission is 10 times less likely when there are preexisting HSV-2 antibodies, compared with primary infection. And the duration of primary HSV-2 infections are reduced in seropositive individuals from 21–28 days to 10–14 days.

Approaches to Vaccine Development. Four approaches have been attempted in developing such a vaccine. Live virus by autoinoculation has been defined as a failure in studies over the past 100 years. HSV has 13 glycoproteins in its envelope, two of which (B and D) are required for infectivity and potent inducers of neutralizing antibodies. Subunit vaccines for glycoprotein B, glycoprotein D, and a combination of B and D are under investigation. Vector glycoprotein genes using either canary pox or a vaccinia vector have been. Engineered herpes simplex virus is a potential future candidate for clinical trials.

Subunit Vaccines. Clinical trials are currently evaluating monoclonal antibody therapy using glycoprotein B and D combinations to treat neonatal HSV infection and HSV encephalitis. Other subunit trials underway include one therapeutic trial of approximately 800 volunteers and 2 primary prevention trials of approximately 500 couples each. In the latter prophylactic trial, one partner in each monogamous relationship has recurrent HSV-2 and the other is HSV-2-seronegative. The former, therapeutic trial is based on the results of a preliminary trial of 100 volunteers between the ages 18 and 55, who averaged 4 to 14 outbreaks per year and had not received acyclovir for 3 months prior to therapy. Half received 100 micrograms of glycoprotein D-2 with alum adjuvant; half received placebo; and there was a booster at 2 months. In those who received the vaccine, the average number of recurrences dropped from 0.5 to 0.42 per month, and the median from 6 to 4 per year.

Genetically Engineered HSV Virus. Genetic stability is a concern in all genetically engineered vaccines; reversions to or recombinations with wild-type viruses, when they do occur, should be less virulent than the current strain. In addition, live attenuated viruses abdicated the ability to become latent and therefore, under some circumstances, might be reactivated. This is why deletions in the gamma 134.5 gene are particularly promising: they debilitate the virus’ ability to become latent and subsequently reactivate (see below).

The herpes simplex virus has a genome that is only 150,000 base pairs (150 kB) long, in an architecture consisting of a unique long segment and a unique short segment. There are internal repeats bonding the unique long and short segments so that the virus could invert upon itself, leaving four equimotor isomers in any population. There is a 70-percent homology between HSV-1 and HSV-2.

The starting point for an engineered vaccine is an intratypic hybrid identified as R-70–20 and was developed about 10 years ago. It consists of the unique long segment of HSV-1, a segment of the unique long segment of HSV-

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