Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1999-03-05
2001-02-27
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S450000, C435S235100, C435S069300, C536S023720
Reexamination Certificate
active
06193984
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of infectious diseases and ophthalmology. More particularly, the invention relates to compositions and methods for vaccination against Herpes Simplex Virus which rely on preparations comprising a mixture of five, six, or seven HSV glycoproteins selected from the group consisting of gB, gC, gD, gE, gG, gH, and gI.
BACKGROUND OF THE INVENTION
A. Incidence and Course of HSV Infection
Herpes Simplex Virus (HSV), also known as
herpesvirus hominis
, is classified into two (2) types, 1 and 2. HSV-1 is transmitted by physical contact, such as kissing, and is thus spread among family members and friends. About half of all babies in the United States are born with IgG antibodies to this agent which is transmitted across the placenta. As this immunity dissipates, new infections are acquired until, by age 45, close to 70% of people have become serologically positive—most without ever experiencing signs of disease, others after one or several episodes of fever blisters or cold sores.
In contrast, HSV-2, also called genital herpes, is transmitted during birth or by sexual contact. The latter's incidence rises with the number of sexual partners and has therefore greatly increased in today's society. Compared with HSV-1, genital herpes is less prevalent overall but is likewise cumulative with age. In addition, genital herpes has engendered considerable anxiety because there is tenuous evidence that it may contribute to the causation of cervical cancer, and because of the risk of vertical transmission during childbirth inducing serious disease. Infections with both causative agents are difficult to childbirth inducing serious disease. Infections with both causative agents are difficult to prevent; and there is as yet no proven vaccine for the prophylaxis of genital herpes. Moreover, an ocular vaccine for the prophylaxis of ocular HSV has not been tried in humans.
Turning specifically to HSV-1, it is the most common infectious cause of blindness in industrial nations. Nesburn, A. B.,
Report of the corneal disease panel: Vision Research: A national plan
1983-1987. Vol. II, part III, edited by Nesburn, A. B., St. Louis, Mo. The often prolonged ocular disease results in considerable visual morbidity, medical expense and loss of productivity in otherwise healthy individuals. Approximately 500,000 cases of ocular HSV-1 are diagnosed annually in the United States alone; and 25% to 45% of these cases may be expected to recur within 1 to 2 years after the primary disease episode. Nesburn, A. B.,
Report of the corneal disease panel: Vision Research: A national plan
1983-1987. Vol. II, part III, edited by Nesburn, A. B., St. Louis, Mo. Of note, the majority of cases diagnosed as primary HSV are actually recurrent infections, as the patient may not recall the antecedent attack. Recurrence is therefore the hallmark of HSV infection.
Following primary infection with herpes simplex virus, the virus establishes a life long latent infection in sensory nerves. At various times during the life of the latently infected individual, the virus may reactivate, travel back to the original peripheral site of infection, and produce recurrent disease. It is these repeated recurrent infections that are responsible for the vast majority of clinically important herpes simplex infections. Therefore, in addition to reducing the incidence and severity of primary infection, an ideal herpes vaccine should also prevent the establishment of latency, thereby eliminating recurrent disease.
After primary HSV infection occurs, the virus can travel in the nerves to the neurons in the trigeminal ganglia, where it then persists throughout life. This critical factor presently makes the herpes simplex infection an incurable disease, since the virus eventually may travel back down these nerves and reinfect the part of the body innervated by that nerve. Various trigger mechanisms such as trauma, fever, sunlight exposure or stress may initiate the reactivation process. This latency-reactivation-recurrence cycle results in ocular virus shedding despite a good local ocular IgA response to the virus. Klein, R. J., Reinfections and site-specific immunity in herpes simplex virus infections.
Vaccine,
7:380-381 (1989). Once HSV has recurred in the eye, corneal disease and stromal scarring can follow, resulting in corneal blindness. Over 1,000 corneal transplants per year are currently performed in the U.S. as a direct result of HSV scarring. Hence, on recovering from the initial HSV infection, the stage is set for reinfection from one's own herpes virus for the remainder of the individual's life.
Since recurrences continue throughout the lifetime of the infected individual, it is clear that natural HSV infection affords insufficient protection against HSV recurrences. Moreover, individuals infected with one HSV serotype are only partially protected against subsequent infection with the other serotype; while individuals with non-ocular HSV-1 are not protected against subsequent ocular HSV-1 infection. Virus from a recurrent lesion on the body can be transferred to the eye, which is thought by some to be a common mode of contracting ocular infections. Because repeated recurrences of HSV do not elicit an immune response that prevents additional recurrences, there is a critical need to elicit a stronger, or perhaps a different immune response than that elicited by natural HSV-1 infection.
With further regard to immune protection, it appears that both antibody and cell-mediated immunity (CMI) are important in the control of HSV infection (Stanberry, L. R. et al., Herpes simplex virus glycoprotein treatment of recurrent genital herpes.
J. Infec. Dis.,
157:156-63 (1988); Kern, A. B. et al., Vaccine Therapy in Recurrent Herpes Simplex,
Arch. Derm.,
89:844-845 (1964); and Frenkel, L. et al., A randomized double blind, placebo-controlled phase 1 trial of a herpes simplex virus purified glycoprotein (gD1) vaccine.
Interscience Conf. on Antimicrobial Agents & Chemo.,
206 (1990), incorporated herein by reference), although CMI may play a larger role. Patients with defects in CMI generally have more severe infection than those with impaired humoral immunity (Berman, P. W. et al., Efficacy of Recombinant Glycoprotein D Subunit Vaccines on the Development of Primary, Recurrent, and Latent Genital Infections With Herpes Simplex Virus Type 2 in Guinea Pigs.
J. Infec. Dis.,
157(5):897-902 (May 1988); Blacklaws, B. et al., Immunogenicity of herpes simplex type 1 glycoproteins expressed in vaccinia virus recombinants.
Virology,
177:727-736 (1990); Spear, P. G., Glycoproteins specified by herpes simplex virus. In:
The herpesviruses
, edited by Roizman, B., New York, Plenum Press, pp. 315-356 (1985); Narrild, B., Humoral response to herpes simplex virus infections. In:
The herpesviruses
, edited by Roizman, B., New York, Plenum Press, pp. 69-86 (1985); and Sarminto, M. et al., Membrane proteins specified by herpes simplex virus III. Role of glycoprotein VP7 (B2) in virion infectivity.
J. Virol.,
29:1149-58 (1979), incorporated herein by reference); whereas patients with frequently recurring HSV have high titers of anti-HSV antibodies. Ophthalmologists have also demonstrated that patients with exuberant immune responses, such as atopes, develop the worst clinical to manifestations of stromal herpetic keratitis. Whereas immunosuppressed patients, in contrast, show exacerbated epithelial keratitis but minimal stromal disease. Hence, immunotherapy capable of inducing a specific higher than normal cellular immune response is needed to combat recurrent ocular HSV infections.
Another factor attributing to recurrent ocular HSV infection is the absence of blood vessels in the cornea. Because the cornea is devoid of blood vessels, systemic immune responses have thus far been inefficient at providing protection from antigenic insults there. Stanberry, L. R. et al., Heterologous Versus Homologous Herpes Simplex Virus Glycoprotein Immunotherapy of Recurrent Genital Herpes.
Pedi
Ghiasi Homayan
Nesburn Anthony B.
Wechsler Steven L.
Cedars-Sinai Medical Center
Lyon & Lyon LLP
Salimi Ali R.
LandOfFree
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