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Institute of Medicine (US) Committee to Study Priorities for Vaccine Development; Stratton KR, Durch JS, Lawrence RS, editors. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington (DC): National Academies Press (US); 2000.

## Vaccines for the 21st Century: A Tool for Decisionmaking.

Show detailsThe herpes simplex virus exists as two biologically distinct serotypes, HSV-1 and HSV-2, which differ mainly by their mode of transmission. Initially, the infection caused by either type is a mucocutaneous infection which is followed later by a latent infection of neuronal cells in the dorsal root ganglia.

The spread of HSV- 1 generally occurs by direct contact, usually involving saliva. This strain of herpes typically presents itself in an infection known as herpes gingivostomatitis. Recurrences of this orolabial infection are commonly called fever blisters or cold sores. Other infections associated with HSV-1 include conjunctivitis, keratitis, and herpetic whitlow. A more serious infection, sporadic encephalitis, appears primarily in older children and adults. In some individuals with chronic skin diseases such as eczema, a severe primary HSV-1 infection known as Kaposi's varicelliform eruption may be encountered.

Acquisition of HSV-2 usually occurs by sexual contact or from a maternal genital infection to a newborn. The most common infection identified with HSV-2 is known as herpes genitalis. HSV-2 is responsible for approximately 85% of symptomatic primary genital HSV infections, most of which are recurrent infections. Some complications associated with genital herpetic infections include aseptic meningitis, extragenital lesions, and neonatal herpes (in the case of maternal transmission).

HSV infection can occur in patients who develop malignancy, an immunodeficiency (i.e., AIDS), or any disease which demands immunosuppressive therapy. The infection may become severe, causing extensive mucocuta-neous necrosis, viremia with dissemination to various organs causing meningoencephalitis, pneumonitis, hepatitis, and coagulopathy.

## DISEASE BURDEN

### Epidemiology

For the purposes of the calculations in this report, the committee estimated that there are 500,000 new oral infections with HSV each year in the United States. These infections occur in people between 1 and 44 years of age. There are approximately 20,000 new ocular infections with HSV each year. These occur in people between 1 and 84 years of age. There are approximately 1,500 cases of central nervous system infection with HSV each year. The incidence was assumed to be highest in children between 5 and 14 years of age. It was also assumed that there are 300,000 new cases of genital HSV infections occurring primarily in people between 15 and 34 years of age. There are also 1,500 new cases of neonatal HSV infections each year. See Table A9–1.

### Disease Scenarios

#### Oral Infections

For the purposes of the calculation in this report, the committee assumed that the vast majority of symptomatic primary oral infections with HSV last 1 week and are associated with an HUI of .9. 2% of the infections are associated with an HUI of .62. It is assumed that 30% of infections are associated with 10 years of minor recurrences (HUI of .9) lasting 1 week and 5% of infections are associated with 5 years of similar recurrences of a longer period per year.

#### Ocular Infections

For the purposes of the calculations in this report, it was assumed that all ocular infections are associated with 2 weeks of an acute conjunctivitis, keratitis, or blepharitis (HUI of .9). It is assumed that 30% of infections become chronic and result in an HUI of .9 for two weeks per year for 10 years.

#### Central Nervous System Infections

For the purposes of the calculations in this report, it was assumed that all CNS HSV infections are associated with a flu-like illness, and that chronic neurologic sequelae of HSV infection occurs in 20% of teenagers and 15% of adults who experience the acute CNS disease. This chronic condition is assumed to be associated with an HUI of .19 for the duration of the person's life.

#### Genital Infections

For the purposes of the calculations in this report, it was assumed that 100% of genital HSV infections are associated with a 2-week period at an HUI of .81 (genital lesions, fever, pain). It is assumed that 90% of infections lead to 10 years of minor recurrences; 10% of infections are associated with 5 years of more severe recurrences.

#### Neonatal Infections

For the purposes of the calculations in this report, it was assumed that 33% of neonatal HSV infections result in acute encephalitis and the other 67% result in serious non-CNS disease. It is assumed that 200 cases of neonatal HSV infection are associated with very severe, chronic neurologic sequelae (an HUI of .19 for approximately 20 years until premature death). See Tables A9–1 and A9–2.

## COST INCURRED BY DISEASE

Table A9–3 summarizes the health care costs incurred by HSV infections.

### Oral and Ocular Infections

For the purposes of the calculation in this report, it was assumed that oral and ocular infections with HSV are associated with costs for medication (over-the-counter and more expensive prescription medications, depending on severity), and physician visits (general or specialists, depending on the severity). A very few cases of severe infections are associated with brief hospitalization.

### Central Nervous System Infections

For the purposes of the calculations in this report, it was assumed that all CNS infections are associated with hospitalization and multiple specialist examinations, plus diagnostic evaluation. Long-term-care costs are included for the few patients who experience lifelong, serious neurologic sequelae.

### Genital Infections

For the purposes of the calculations in this report, it was assumed that genital HSV infections are associated with outpatient treatment consisting of physician visits, occasional diagnostic evaluation, and medication. The frequency of physician visits increases with the severity of the recurrences.

### Neonatal Infections

For the purposes of the calculations in this report, it was assumed that all neonates infected with HSV require hospitalization. It was assumed that hospitalization costs for encephalitis are higher than for the non-encephalitic manifestations. Additional costs related to labor and delivery of the neonate are included. Long-term-care costs are included for the few patients who experience lifelong serious neurologic sequelae from neonatal infections.

## VACCINE DEVELOPMENT

The committee assumed that it will take 7 years until licensure of a HSV vaccine and that $240 million needs to be invested. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report.

## VACCINE PROGRAM CONSIDERATIONS

### Target Population

For the purposes of the calculations in this report, it is assumed that the target population for this vaccine is all adolescents (age 12 years). It was assumed that 50% of the target population would utilize the vaccine.

### Vaccine Schedule, Efficacy, and Costs

For the purposes of the calculations in this report, it was estimated that this vaccine would cost $50 per dose and that administration costs would be $10 per dose. Default assumptions of a 3-dose series and 75% efficacy were accepted. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report.

## RESULTS

If a vaccine program for HSV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be 28,000. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 7,500. Most of the disease burden is associated with genital and CNS infections due to the large number of genital infections and the serious, chronic sequelae associated with the relatively fewer cases of CNS HSV disease.

If a vaccine program for HSV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the health care costs saved would be $850 million. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the health care costs saved would be $225 million.

If a vaccine program for HSV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the program cost would be $680 million. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the program cost would be $240 million.

Using committee assumptions of time and costs until licensure, the fixed cost of vaccine development has been amortized and is $7.2 million for a HSV vaccine.

If a vaccine program were implemented today and the vaccine were 100% efficacious and utilized by 100% of the target population, the annualized present value of the cost per QALY gained is -$6,000. A negative value represents a saving in costs in addition to a saving in QALYs. Using committee assumptions of less-than-ideal utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the cost per QALY gained is $3,000.

See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported.

## READING LIST

- Hirsch MS. Herpes Simplex Virus. In: Principles and Practice of Infectious Diseases. GL Mandell, editor; , JE Bennett, editor; , Dolin R, editor. eds. New York, NY: Churchill Livingstone, 1995, pp.1336–1345.
- Institute of Medicine. New Vaccines Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, DC: National Academy Press, 1985. a.
- Koelle DM, Benedetti J, Langenberg A, et al. Asymptomatic Reactivation of Herpes Simplex Virus in Women after the First Episode of Genital Herpes. Annals of Internal Medicine 1992; 116:433–437. [PMC free article: PMC4084907] [PubMed: 1310837]
- Kohl S. Postnatal Herpes Simplex Virus Infection. In: Textbook of Pediatric Infectious Diseases. RD Feigin, editor; and JD Cherry, editor. eds. Philadelphia, PA: WB Saunder Company, 1992, pp.1558–1583.
- U.S. Bureau of the Census. Statistical Abstract of the U.S.: 1995 (115
^{th}edition.) Washington, DC. 1995. - Ventura SJ, Martin JA, Mathews TJ, et al. Advance Report of Final Natality statistics, 1994. Monthly Vital Statistics Report 1996; 44. [PubMed: 9666678]

## Footnotes

See Appendix 28 for more information.

- Herpes Simplex Virus - Vaccines for the 21st CenturyHerpes Simplex Virus - Vaccines for the 21st Century

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