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Vaccines for the 21st Century: A Tool for Decisionmaking (2000)

Chapter: Appendix 9: Herpes Simplex Virus

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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

APPENDIX 9
Herpes Simplex Virus

The 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-

See Appendix 28 for more information.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

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

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Table A9–1 Incidence and Mortality of HSV Infections

Age Groups

Populations

Incidence Rates (per 100,000)

% Distribution of Cases

Cases

INCIDENCE OF ORAL HSV INFECTIONS

<1

3,963,000

0.00

0.0000

0

1–4

16,219,000

1,541.40

0.5000

250,000

5–14

38,056,000

394.16

0.3000

150,000

15–24

36,263,000

137.88

0.1000

50,000

25–34

41,670,000

60.00

0.0500

25,000

35–44

42,149,000

59.31

0.0500

25,000

45–54

30,224,000

0.00

0.0000

 

55–64

21,241,000

0.00

0.0000

 

65–74

18,964,000

0.00

0.0000

 

75–84

11,088,000

0.00

0.0000

 

85+

3,598,000

0.00

0.0000

 

Total

263,435,000

189.80

1.0000

500,000

INCIDENCE OF OCULAR HSV INFECTIONS

<1

3,963,000

0.00

0.0000

0

1–4

16,219,000

6.17

0.0500

1,000

5–14

38,056,000

7.88

0.1500

3,000

15–24

36,263,000

8.27

0.1500

3,000

25–34

41,670,000

7.20

0.1500

3,000

35–44

42,149,000

4.75

0.1000

2,000

45–54

30,224,000

6.62

0.1000

2,000

55–64

21,241,000

9.42

0.1000

2,000

65–74

18,964,000

10.55

0.1000

2,000

75–84

11,088,000

18.04

0.1000

2,000

85+

3,598,000

0.00

0.0000

0

Total

263,435,000

7.59

1.0000

20,000

INCIDENCEE OF HSV CNS INFECTION

<1

3,963,000

0.00

0.0000

 

1–4

16,219,000

0.00

0.0000

 

5–14

38,056,000

1.97

0.5000

750

15–24

36,263,000

0.00

0.0000

 

25–34

41,670,000

0.00

0.0000

 

35–44

42,149,000

0.00

0.0000

 

45–54

30,224,000

0.62

0.1250

188

55–64

21,241,000

0.88

0.1250

188

65–74

18,964,000

0.99

0.1250

188

75–84

11,088,000

1.69

0.1250

188

85+

3,598,000

0.00

0.0000

 

Total

263,435,000

0.57

1.0000

1,500

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Age Groups

Populations

Incidence Rates (per 100,000)

% Distribution of Cases

Cases

MORTALITY ASSOCIATED WITH HSV CNS INFECTION

<1

3,963,000

0.00

0.0000

 

1–4

16,219,000

0.00

0.0000

5–14

38,056,000

0.39

0.2222

150

15–24

36,263,000

0.00

0.0000

 

25–34

41,670,000

0.00

0.0000

35–44

42,149,000

0.00

0.0000

45–54

30,224,000

0.43

0.1944

131

55–64

21,241,000

0.62

0.1944

131

65–74

18,964,000

0.69

0.1944

131

75–84

11,088,000

1.18

0.1944

131

85+

3,598,000

0.00

0.0000

 

Total

263,435,000

0.26

1.0000

675

INCIDENCE OF GENITAL HSV INFECTION

<1

3,963,000

0.00

0.0000

 

1–4

16,219,000

0.00

0.0000

5–14

38,056,000

0.00

0.0000

15–24

36,263,000

275.76

0.3333

100,000

25–34

41,670,000

479.96

0.6667

200,000

35–44

42,149,000

0.00

0.0000

 

45–54

30,224,000

0.00

0.0000

55–64

21,241,000

0.00

0.0000

65–74

18,964,000

0.00

0.0000

75–84

11,088,000

0.00

0.0000

85+

3,598,000

0.00

0.0000

Total

263,435,000

113.88

1.0000

300,000

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.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×
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.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Table A9–2 Disease Scenarios for HSV Infection

 

No. of Cases

% of Cases

Committee HUI Values

Duration (years)

ORAL

asymptomatic primary infection

 

80%

 

symptomatic primary infection

490,000

98.0%

 

gingivostomatitis, pharyngitis, fever

 

0.90

0.0192 (1 week)

severe primary infection

 

2.0%

 

gingivostomatitis, pharyngitis, fever

10,000

 

0.62

0.0192 (1 week)

minor recurrences

150,000

30.0%

0.90

0.0192 (1 week)

serious recurrences

25,000

5.0%

0.90

0.0384

OCULAR

Primary infection

20,000

100.0%

 

blepharitis, conjunctivitis, keratitis

 

0.90

0.0384 (2 weeks)

Recurrences

6,000

30.0%

0.90

0.0384 (2 weeks)

CNS (ENCEPHALITIS, MENINGITIS)

Acute infection

1,500

100.0%

 

flu-like symptoms, CNS disturbance

 

0.19

0.0833 (1 month)

Chronic neurologic sequelae—children/teenagers

300

20.0%

 

severe neurologic impairment for 20-year period

 

0.19

20.0000 (20 years)

death after 20 years impairment

 

0.00

2 1.7793 (discounted quality adjusted life expectancy at age 30)

Chronic neurologic sequelae—adults

225

15.0%

 

severe neurologic impairment for 10-year period

 

0.19

10.0000 (10 years)

death after 10 years impairment

 

0.00

8.5536 (discounted quality adjusted life expectancy at age 70)

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

 

No. of Cases

% of Cases

Committee HUI Values

Duration (years)

GENITAL

Acute symptomatic infection

300,000

100.0%

 

genital lesions, pain, fever

 

0.81

0.0384 (2 weeks)

Minor recurrence

270,000

90.0%

0.95

0.0384 (2 weeks)

Serious recurrence

30,000

10.0%

 

NEONATAL HSV

Acute non-encephalitis

1,000

66.7%

0.24

0.0833 (1 month)

Acute encephalitis

500

33.3%

0.24

0.0833 (1 month)

Chronic neurologic sequelae

200

13.3%

 

severe neurologic impairment for 20-year period

 

0.19

20.0000 (20 years)

death after 20 years impairment

 

0.00

47.0252 (discounted quality adjusted life expectancy at age 20)

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.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Table A9–3 Health Care Costs Associated with HSV Infection

 

% of Cases

% with Care

Cost per Unit

Units per Case

Form of Treatment

ORAL

 

Symptomatic primary infection

98.0%

 

gingivostomatitis, pharyngitis, fever

 

100%

$10

1.0

medication a

 

10%

$50

1.0

physician a

Severe primary infection

2.0%

 

gingivostomatitis, pharyngitis, fever

 

10%

$3,000

1.0

hospitalization

 

 

100%

$100

1.0

physician b

100%

$50

1.0

medication b

100%

$50

1.0

diagnostic a

Minor recurrences

30.0%

 

 

 

100%

$50

1.0

physician a

100%

$50

1.0

medication b

Serious recurrences

5.0%

 

 

 

100%

$50

2.0

physician a

100%

$50

2.0

medication b

OCULAR

 

Primary infection

100.0%

 

blepharitis, conjunctivitis, keratitis

 

100%

$50

1.0

medication a

 

100%

$50

1.0

physician a

Recurrences

30.0%

 

30% of primary cases 1 per year for 10 years

 

100%

$50

1.0

medication a

 

25%

$50

1.0

physician a

CNS

 

Acute infection

100.0%

 

flu-like symptoms, CNS disturbance

 

100%

$6,000

1.0

hospitalization

 

 

100%

$1,500

15.0

physician c

100%

$500

2.0

diagnostics c

Chronic neurologic sequelae—children/teenagers

20.0%

 

severe neurologic impairment for 20 year period

 

100%

$225

365.0

Institutional care (per year)

Chronic neurologic sequelae—adults

15.0%

 

severe neurologic impairment for 10 year period

 

100%

$225

365.0

Institutional care (per year)

GENITAL

 

Acute symptomatic infection

100.0%

 

genital lesions, pain, fever

 

100%

50%

1.0

physician a

 

 

100%

$50

1.0

medication b

50%

$50

1.0

diagnostic a

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

 

% of Cases

% with Care

Cost per Unit

Units per Case

Form of Treatment

Minor recurrence

90.0%

 

 

 

100%

$50

1.0

physician a (per year)

100%

$50

1.0

medication b (per year)

Serious recurrence

10.0%

 

 

 

100%

$50

4.0

physician a

100%

$50

4.0

medication b

NEONATAL HSV

 

Acute non-encephalitis

66.7%

 

 

 

100%

$7,000

1.0

hospitalization

100%

$150

28

physician b

100%

$500

4.0

diagnostic c

100%

$1,000

1

additional delivery costs

Acute encephalitis

33.3%

 

 

 

100%

$12,000

1.0

hospitalization

100%

150

28.0

physician c

100%

$500

4.0

diagnostic c

100%

$1,000

1.0

additional delivery costs

Chronic neurologic sequelae

13.3%

 

 

100%

$225

365.0

Institutional care (per year)

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.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

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, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 1336–1345.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Institute of Medicine. New Vaccines Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, DC: National Academy Press, 1985a.


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.

Kohl S. Postnatal Herpes Simplex Virus Infection. In: Textbook of Pediatric Infectious Diseases. RD Feigin and JD Cherry eds. Philadelphia, PA: WB Saunder Company, 1992, pp. 1558–1583.


U.S. Bureau of the Census. Statistical Abstract of the U.S.: 1995 (115th 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.

Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Suggested Citation:"Appendix 9: Herpes Simplex Virus." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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Vaccines have made it possible to eradicate the scourge of smallpox, promise the same for polio, and have profoundly reduced the threat posed by other diseases such as whooping cough, measles, and meningitis.

What is next? There are many pathogens, autoimmune diseases, and cancers that may be promising targets for vaccine research and development.

This volume provides an analytic framework and quantitative model for evaluating disease conditions that can be applied by those setting priorities for vaccine development over the coming decades. The committee describes an approach for comparing potential new vaccines based on their impact on morbidity and mortality and on the costs of both health care and vaccine development. The book examines:

  • Lessons to be learned from the polio experience.
  • Scientific advances that set the stage for new vaccines.
  • Factors that affect how vaccines are used in the population.
  • Value judgments and ethical questions raised by comparison of health needs and benefits.

The committee provides a way to compare different forms of illness and set vaccine priorities without assigning a monetary value to lives. Their recommendations will be important to anyone involved in science policy and public health planning: policymakers, regulators, health care providers, vaccine manufacturers, and researchers.

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