Study of the Safety of a Particular Herpes Vaccine in Adults With or Without Herpes Infection

Herpes simplex virus 2 (HSV-2) causes genital herpes and increases the risk of acquisition
and transmission of HIV. An HSV-2 vaccine is not available. We will study a
replication-defective HSV-2 vaccine, HSV529, that is deleted for 2 essential viral proteins,
that can infect, but not replicate in normal cells. The goals of the study are to determine
(a) the safety of HSV529 vaccine in persons with or without HSV infection, and (b) the
ability of the vaccine to elicit immune responses to HSV-2 including virus-specific
antibodies and T cell responses to the virus. Three groups of 20 subjects each will be
randomized and will receive 3 doses of HSV529 (15 subjects per group) or saline placebo
injection (5 subjects per group). Each subject will be followed for 6 months after the last
dose of vaccine. The 3 groups will be (a) subjects who were infected with HSV-2 in the past
but may or may not have been infected with HSV-1 (HSV-1+/-/HSV-2+), (b) subjects who have
been infected only with HSV-1 (HSV-1+/HSV-2-), and (c) subjects who have not been infected
with HSV-1 or HSV-2 (HSV-1-/HSV-2-). Vaccine or placebo will be administered on Day 0 and
approximately 1 month and 6 months after enrollment.

- INCLUSION CRITERIA:

An individual must fulfill all of the following criteria in order to be eligible for trial
enrollment:

1. Aged 18 to 40 years on the day of enrollment.

2. In good general health with absence of significant health problems as determined by
medical history, physical examination, and laboratory screening performed during
screening visits.

3. Subject will reside within a 60 mile or less radius from Bethesda, MD during the
period of participation in the trial.

4. Hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, and
liver function (ALT, AST, alkaline phosphatase, total bilirubin) screening laboratory
results do not fall into the range of values that are Grade 1 or greater as per the
toxicity grading scale and IgG level greater than or equal to 600 mg/dl.

5. Females subjects must be of non-childbearing potential i.e. surgically sterilized
(bilateral tubal ligation, hysterectomy) or, if of child-bearing potential and
sexually active with a male partner, she must be willing to use a highly effective
method of contraception (e.g., intrauterine device (IUD); oral contraceptives
diaphragm or condom in combination with contraceptive foam, jelly or cream; Norplant,
DepoProvera, contraceptive skin patch or cervical ring) for at least 30 days prior to
vaccination and until 30 days after final vaccination or be in a monogamous
relationship with a male partner who has undergone a vasectomy at least 6 months prior
to first dose of study agent.

6. Willingness to attend all scheduled visits and able to comply with all trial
procedures (e.g., blood draws, completion of diary cards, return for follow-up visits,
accessible by phone or pager, able to self-sample for assessment of asymptomatic
shedding of HSV, and not planning on moving from study area).

7. Negative HIV test result determined with an approved FDA-approved test. Confirmatory
testing may be required based on the initial assay used and the result.

8. Subject is willing not to use antiviral therapy less than or equal to 2 days before
and less than or equal to 3 days after each injection.

9. Subject is willing to forgo receipt of a licensed, live vaccine in the 30 days
preceding each dose of vaccine or in the 30 days following each dose of vaccine. The
inactivated flu vaccine can be used greater than or equal to 14 days before or greater
than or equal to 14 days after administration of study vaccine, if this is felt to be
necessary.

10. Persons who have close contact with infants or immunocompromised individuals agree to
avoid such contact for 3 days after each injection.

11. Subject must be either HSV-1 IgG antibody positive or negative and HSV-2 IgG antibody
positive, HSV-1 IgG antibody positive /HSV-2 IgG antibody negative, or HSV-1/HSV-2 IgG
antibody negative as determined by an available commercial immunoassay.

12. Subject must be willing to allow storage of blood, swabs of skin or mucosa, biopsies
of skin lesions, or, for female subjects, cervicovaginal secretions (if collected) for
future research.

Participation of Women:

Contraception: The effects of HSV529 on the developing human fetus are unknown. For this
reason, females subjects must be of non-childbearing potential i.e. either surgically
sterilized (bilateral tubal ligation, hysterectomy) or, if of child-bearing potential and
sexually active with a male partner, she must be willing to use a highly effective method
of contraception (e.g., intrauterine device (IUD); oral contraceptives diaphragm or condom
in combination with contraceptive foam, jelly or cream; Norplant, DepoProvera,
contraceptive skin patch or cervical ring) for at least 30 days prior to vaccination and
until 1 month after final vaccination or be in a monogamous relationship with a male
partner who has undergone a vasectomy at least 6 months prior to first dose of study agent.
Females must have a negative urine pregnancy test result prior to injection with HSV529 or
placebo. During the course of the study, if a woman becomes pregnant or suspects she is
pregnant, she should inform the study staff and her primary care physician immediately.

EXCLUSION CRITERIA:

Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than
enrollment into observational studies or into the screening protocol. Study staff should be
notified of co-enrollment as it may require the approval by the Principal Investigator.

An individual fulfilling any of the following criteria is to be excluded from trial
enrollment:

1. Subject is pregnant or lactating OR planning to become pregnant timeframe that begins
30 days prior to the first vaccination and ends 30 days after the third vaccination.

2. Body Mass Index greater than 40.

3. Participation in another clinical trial investigating a vaccine, drug, medical device,
or medical procedure in the 4 weeks preceding the first trial vaccination or or
planned participation during the study period up to 6 months after the last dose of
vaccine or placebo. The non-interventional follow-up for an earlier study (e.g.,
long-term surveillance) will be allowed.

4. Severe active infection or serious HSV-2 related or unrelated medical conditions that,
in the opinion of the investigator, would prevent study completion.

5. Subjects with 6 or more symptomatic recurrences of genital herpes disease within the
year prior to Day 0.

6. A history of HSV infection of the eye (e.g., herpes simplex interstitial keratitis or
uveitis).

7. A history of herpes gladiatorum, herpetic whitlow or eczema herpeticum.

8. A history of lesions caused by HSV on either arm.

9. A history of herpes-associated erythema multiforme.

10. A history of a clinically significant autoimmune disorder.

11. Known or suspected congenital or acquired immunodeficiency

12. Receipt of anti-cancer chemotherapy or radiation therapy within the preceding 6
months.

13. Subjects using corticosteroids (excluding topical, inhaled or nasal) or any
immunomodulating drugs within 42 days prior to the first vaccination. An
immunosuppressive dose of corticosteroids is defined as greater than or equal to 10 mg
prednisone equivalent per day for greater than or equal to 14 days.

14. Subjects without a spleen.

15. Subjects receiving immunoglobulin within the past 6 months or anticipated receipt of
immunoglobulin during the 28 days following vaccination.

16. Bleeding disorder, or receipt of anticoagulants that, in the opinion of the
Investigator, would interfere with the subject s participation in the trial.

17. Prior vaccination against herpes simplex virus.

18. Known allergy or intolerance to vaccine components [e.g., potassium glutamate
(possible cross-reaction to monosodium glutamate), sucrose] or to a vaccine containing
any of the same substances.

19. Deprived of freedom by an administrative or court order, or in an emergency setting,
or hospitalized involuntarily.

20. Current alcohol abuse or drug abuse or addiction.

21. Chronic illness that, in the opinion of the Investigator, is at a stage where it might
interfere with trial conduct or completion.

22. Employee of the NIH or contractor working at the NIH, with direct involvement in the
proposed study as well as family members (i.e. immediate, husband, wife and their
children, adopted or natural) of the employee or of the investigators of this study.

23. Any condition that the PI thinks might compromise the person s ability to comply with
the requirements of the study.

Justification for Exclusion of Women and Children:

Exclusion of Women:

- Pregnancy: Pregnant women are excluded from this study because the effects of HSV529
on the developing human fetus are unknown with the potential for teratogenic or
abortifacient effects.

- Breast-feeding: Because there is an unknown but potential risk for adverse events in
nursing infants secondary to vaccination of the mother with HSV529, breastfeeding
should be discontinued if the mother will be vaccinated with HSV529.

Exclusion of Children:

Because there are insufficient data regarding dosing or adverse events available in adults
to judge the potential risk in children, children are excluded from this study.