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New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries (1986)

Chapter: Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae

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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Appendix D-17
The Prospects for Immunizing Against Streptococcus pneumoniae

DISEASE DESCRIPTION

Streptococcus pneumoniae is a major cause of three infections: pneumonia, otitis media, and meningitis (Austrian, 1984). The organism is a component of the normal bacterial flora of the human upper respiratory tract; it invades the lower respiratory tract or middle ear by direct extension from the nasopharynx when anatomic or physiologic defenses are compromised, most frequently by antecedent viral infection. Meningitis may occur either as a sequel to bacteremia secondary to pneumonia, or as a direct extension from an infected paranasal sinus or mastoid; or it may follow fracture of the skull. The pneumococcus also can infect other serous cavities, including the pleura, joints, peritoneum, and pericardium, and it is a cause of acute bacterial endocarditis.

Colonization of the nasopharynx with pneumococci may begin within 24 hours of birth. Defense against infection, once established, depends on phagocytosis of the bacteria by polymorphonuclear leukocytes in the presence of type-specific anticapsular antibody and complement.

Recovery from pneumococcal pneumonia usually results in restoration of the lung to its normal state. One or more attacks of pneumococcal otitis media may be followed by transient or permanent hearing impairment, either of which may retard learning. Pneumococcal meningitis has a high mortality rate, both in infancy and in the elderly, exceeding 40 percent in treated adults over age 40. Permanent neurologic damage follows pneumococcal meningitis in about 40 percent of children who survive the disease.

The committee gratefully acknowledges the efforts of R.Austrian, who prepared major portions of this appendix, and the advice and assistance of F.W.Denny and J.B.Robbins. The committee assumes full responsibility for all judgments and assumptions.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Limitations of Existing Vaccines

Polyvalent vaccines of killed whole pneumococcal cells were developed in the second decade of the twentieth century to prevent epidemic pneumococcal pneumonia in industrial populations, and they were shown to be safe. Demonstration of their efficacy remained uncertain, however, because of the design of trials employed for that purpose. Vaccines of purified capsular polysaccharides, introduced in the 1930s, were shown unequivocally to protect against infection with the types represented in them in the 1940s. In addition, the vaccine was shown to reduce by about half the likelihood of colonization of the upper respiratory tract with pneumococcal types represented in the vaccine. Vaccination had no demonstrable effect on previously established carriage of a type represented in the vaccine.

Vaccines composed of the purified polysaccharides of pneumococcal types responsible for the majority of pediatric infections have proved to be poorly immunogenic and to provide little or no protection against infection. Similar vaccines for the prevention of infection with H. influenzae and N. meningitidis group C also have been ineffective.

More details of the limitations of existing vaccines can be found in the recent review by Austrian (1984).

PATHOGEN DESCRIPTION

Streptococcus pneumoniae is a gram-positive capsulated coccus found commonly in pairs and is a normal inhabitant of the human upper respiratory tract. More than 80 capsular serotypes are known, each distinguished by the unique polysaccharide structure of its capsule. All serotypes are not equally invasive; about 90 percent of bacteremic infections are caused by 23 serotypes. The frequency with which different pneumococcal serotypes cause infection in infants and young children and in adults differs. In the pediatric population, pneumococcal types 6A, 6B, 14, 19F, 19A, and 23F account for more than half of all pneumococcal infections. In adults, types 1, 3, 4, 7F, 8, and 12F are seen more commonly. The currently licensed vaccine, which contains 23 capsular polysaccharides, includes antigens from types found at all ages. The chemical compositions of many of the polysaccharides in the U.S.-licensed vaccine are known.

HOST IMMUNE RESPONSE

In the normal human host, defense against invasion of internal bodily sites by pneumococci depends primarily on type-specific serum antibodies to pneumococcal capsular polysaccharides. This conclusion is based on epidemiologic studies of pneumococcal infections in man, on experiments in a variety of susceptible animal species, and on the therapeutic effect of type-specific anticapsular antiserum in the treatment of pneumococcal pneumonia prior to the advent of sulfonamides and antibiotics. In addition, previous trials in adults of vaccines of

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

purified pneumococcal capsular polysaccharides have shown that they are effective in stimulating type-specific immunity. Recovery from natural infection with a given pneumococcal type usually is followed by lifelong immunity to reinfection with that type.

Type-specific capsular antibodies of the IgG class may be transferred transplacentally from mother to fetus during pregnancy and provide some protection against infection with homologous types during the first 6 months of life. Maximum attack rates of pneumococcal infection, including otitis media and bacteremia, occur between the ages of 6 months and 2 years. Initial immunologic responses to vaccination with pneumococcal capsular polysaccharides in infancy are predominantly of the IgM class, and the protection afforded by such antibodies is of limited duration, usually not exceeding 6 months. The ability to respond to different pneumococcal capsular polysaccharides develops at different ages; immunity to type 3 capsular polysaccharide is observed as early as age 6 months. Responsiveness to the serotypes responsible for the majority of infections in early life (types 6A, 6B, 14, 19F, 19A, and 23F) may be delayed until the age of 4 or later. Preliminary studies of type 6A pneumoccocal capsular polysaccharide coupled to tetanus toxoid suggest that responsiveness to the conjugated antigen occurs at a significantly earlier age and induces IgG as well as IgM antibodies.

Limited data on the responsiveness of the elderly to parenteral administration of pneumococcal capsular polysaccharides suggest that, although they respond somewhat less vigorously than young adults, their responses are significant and result in protection against infection. Patients who have acquired immunologic deficiencies, such as those resulting from lymphocytic malignancies (e.g., multiple myeloma) respond feebly or not at all to the current polyvalent pneumococcal vaccine.

DISTRIBUTION OF DISEASE

Geographic Distribution

Pneumococcal pneumonia, otitis media, and meningitis occur throughout the world and have been found to be endemic wherever they have been sought. Higher than average attack rates have been observed in populations living in depressed socioeconomic conditions and in association with movement from rural to urban environments. Epidemics also may occur under conditions in which immunologically naive adults are congregated in industrial or military barracks, the so-called “recruit disease” phenomenon.

Disease Burden Estimates

The burden of pneumococcal infection is large, but it is difficult to obtain accurate data on the incidence of pneumococcal pneumonia and pneumococcal otitis media for a variety of reasons. The incidence of

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

pneumococcal meningitis is easier to document, in part because the clinical picture is more clearly defined. The estimates below are largely developed from the review by Austrian (1984).

The diagnosis of pneumococcal pneumonia on the basis of recovery of the organism from expectorated pulmonary secretions is uncertain because of contamination with organisms from the upper respiratory tract. The diagnosis can be established by direct recovery of pneumococci from the lower respiratory tract by transtracheal aspirate or lung puncture, but the routine employment of these invasive procedures cannot be justified on ethical grounds. The diagnosis can be confirmed also by isolation of the organism from the blood of approximately 25 percent of cases, by its recovery from a metastatic focus of infection, by demonstration of capsular polysaccharide in the blood or urine, or by the demonstration of antibodies developing in response to infection. Most of these procedures require isolation and identification of the capsular type of the organism. This may not be possible because the necessary micro-biological techniques have been abandoned by most routine diagnostic laboratories since the advent of antibiotics. The problem is confounded further by frequent failures to obtain material for culture prior to the initiation of antibacterial therapy, a practice that may preclude subsequent recovery of the organism causing illness. Diagnosis of the cause of otitis media is made infrequently today because tympanocentesis to recover the infecting organism from the middle ear is practiced only in a few clinical settings. Despite these limitations, sufficient data are available to estimate the disease burdens resulting from these two pneumococcal infections in some areas.

Studies of different populations in the United States have found attack rates of pneumococcal pneumonia that range from 1.5 to 10 cases per 1,000 persons per year. In general, the attack rate in developed countries is probably between 1 and 5 per 1,000 persons per year. Attack rates are highest in infancy and in persons over 50 years of age.

In some settings, the attack rate of pneumococcal pneumonia may reach 100 per 1,000 persons per year, as in gold mining novices in South Africa. Reports in central African medical journals indicate that in several countries the disease also occurs with high frequency in persons migrating from rural settings to urban centers.

One method of estimating disease burden for pneumococcal pneumonia in the developing world is to assume that rates are similar to those reported for lobar pneumonia in the United States during the 1920s, that is, prior to any antibiotic use.

Age-specific rates used in Table D-17.1 are adapted from Heffron (1939). Hypothetical age-specific case fatality rates for untreated cases of pneumococcal pneumonia are also shown in Table D-17.1 and reflect both the estimated overall rate of 20 to 40 percent (American Public Health Association, 1985; Austrian, 1984) for untreated cases in the United States, and the recognition that mortality is greatest in the extremes of age. Morbidity categories were assigned (Table D-17.2) to reflect the overall severity of pneumococcal pneumonia. Population estimates for calculating numbers of cases in the developing world are from the Population Reference Bureau (1984) (also see Chapter 4). Disease burden estimates for pneumococcal pneumonia are shown in Table D-17.3.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.1 Incidence Rates and Case Fatality Rates for Pneumococcal Pneumonia by Age

Age Group

Incidence Ratea (per 1,000)

Case Fatality Rateb (percent)

Under 5 years

17.15

40

5–14 years

9.99

20

15–59 years

9.59

10

60 years and over

26.28

50

Overall

11.82

24

aAdapted from Heffron (1939).

bAdapted from American Public Health Association (1985).

TABLE D-17.2 Pneumococcal Pneumonia: Distribution of Morbidity Categories by Age

 

Morbidity Category (percent distribution)

Age Group

A

B

C

Under 5 years

10

20

70

5–14 years

10

40

50

15–59 years

10

40

50

60 years and over

10

10

80

Estimates (particularly for deaths) derived from this method are considerably higher than estimates derived in Appendix B for pneumococcal pneumonia in the under 5 and 5 to 14 years age groups. The estimates in Appendix B are derived from recent case reporting in developing countries, whereas those in Table D-17.3 are derived from reporting in the United States in the 1920s. One possible reason for this discrepancy is that a proportion of lobar pneumonia cases included in these rates may be due to organisms other than S. pneumoniae, such as Hemophilus influenzae, and Staphylococcus pyogenes. Radiological diagnoses also are not always consistent. Rates vary widely in different times and with differing socioeconomic circumstances. Thus, a wide range of estimates will arise when they are based on different studies. Another possible reason for the discrepancy is the likelihood that estimates in Appendix B reflect antibiotic use in certain regions

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.3 Disease Burden: Pneumococcal Pneumonia

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

855,030

5

908,457

4

1,874,585

4

610,605

6

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

1,710,061

7

3,633,826

6

7,498,340

6

610,605

8

C

Severe pain, severe short-term impairment, or hospitalization

5,985,213

10

4,542,283

9

9,372,926

9

4,884,842

12

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

 

n.a.

 

n.a.

 

n.a.

 

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

 

n.a.

 

n.a.

 

n.a.

 

n.a.

F

Total impairment

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

3,420,122

n.a.

1,816,913

n.a.

1,874,585

n.a.

3,053,026

n.a.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.4 Incidence Rates and Case Fatality Rates for Isolated Pneumococcal Bacteremia by Age

Age Group

Incidence Rate (per 1,000)

Case Fatality Rate (percent)

Under 5 years

1.5

10

5–14 years

0.5

5

15–59 years

0.19

2.5

60 years and over

1.0

12.5

Overall

0.5

7.5

for severe cases of pneumonia, whereas those in Table D-17.3 are based on rates for untreated cases. The approach adopted to determine the effect of this uncertainty on the ultimate ranking of an improved vaccine against S. pneumoniae is discussed below.

Retrospective studies of pneumococcal bacteremia, which significantly underestimate its incidence because of the failure to routinely obtain blood cultures or to obtain them only after initiation of therapy, suggest an incidence of 9 cases per 100,000 persons per year for the U.S. population at large. For children under age 2, the annual rate is 30 to 40 per 100,000 persons, and for those 60 years of age and older, it is about 20 per 100,000 persons (Austrian, 1984). The true incidence is probably two to five times that recorded. The mortality of bacteremic pneumococcal pneumonia is four times that of putative pneumococcal pneumonia in the absence of bacteremia, whether the cases compared are treated or nontreated.

For the purposes of this report, it is assumed that the overall incidence rate for pneumococcal bacteremia in the developing world is 1 per 1,000 per year, or about twice the estimated maximum U.S. rate of 50 per 100,000 per year (Austrian, personal communication, 1984). One-half of cases, however, are assumed to occur concomitantly with pneumonia (Health and Public Policy Committee, 1986) and meningitis, so that the rate for bacteremia without other chemical manifestations is 0.5 per 1,000 per year. The variation of incidence rates by age is assumed to be similar to that of U.S. rates, and is shown in Table D-17.4. Actual rates are about half those in the United States since cases with pneumonia and meningitis are counted in other tables. Case fatality rates, also shown in Table D-17.4, are distributed by age like those for pneumonia. However, they are lower because more severe cases with pneumonia and meningitis are counted elsewhere. It should be stressed that these figures are crude estimates; true incidence and case fatality rates for isolated pneumococcal bacteremia are not known.

Morbidity categories (Table D-17.5) are assigned to reflect generally more severe disease at the extremes of age. Disease burden estimates for pneumococcal bacteremia are shown in Table D-17.6.

Pneumococcal otitis media is one of the most common illnesses seen in pediatric practices—an estimated 20 percent of all children born in

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.5 Pneumococcal Bacteremia: Distribution of Morbidity Categories by Age

 

Morbidity Category (percent distribution)

Age Group

A

B

C

Under 5 years

30

30

40

5–14 years

40

30

30

15–59 years

40

30

30

60 years and over

30

30

40

the United States will experience an attack of pneumococcal otitis media in the first 2 years of life. Pneumococcus is the cause of one-half to two-thirds of all bacterial otitis media. The disease appears to be even more common among American Indians and Eskimos than it is in Caucasians. It may be complicated by mastoiditis or meningitis and may be followed by chronic otitis with permanent hearing impairment. For the purposes of this report, it is assumed that three-fourths of children in the developing world have an episode of otitis by age 5 years, and that two-thirds of these are pneumococcal (Austrian, 1984).

This assumption yields a crude incidence rate of 500 per 1,000 per 5 years or 100 per 1,000 per year (10 percent). This is in good agreement with empirical studies, such as the findings of a 15 percent yearly incidence rate for pneumococcal otitis media in children under age 5 reported by Mäkalä et al. (1983).

Assignment to morbidity categories for otitis media is estimated as follows: 50 percent of cases to category A, 30 percent category to B, and 20 percent to category C. In addition, chronic hearing loss is estimated to occur in mild form (category D) in 10 percent of untreated survivors, and in severe form (category E) in 1 percent. Disease burden estimates for pneumococcal otitis media are shown in Table D-17.7. Death is assumed to result in 1 percent of severe cases.

The pneumococcus is the second most common cause of bacterial meningitis in interepidemic periods of meningococcal infection. The annual U.S. attack rate is about 1.5 per 100,000 persons. Incidence rates are highest at the extremes of life, and both neurologic sequelae and mortality are common despite specific antipneumococcal therapy. Deaths in treated neonates and persons over age 60 exceed 50 percent. Similar data from other areas confirm the lethality of the infection. It has been estimated that the annual attack rate of pneumococcal meningitis in West Africa is about 14 per 100,000 persons (Diop Mar et al., 1979), almost ten times that in developed countries.

For the purposes of this report, incidence rates and case fatality rates for the developing world are taken from Cadoz et al. (1981; Figure 2 and Table 3 respectively). These rates are for hospitalized

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.6 Disease Burden: Pneumococcal Bacteremia

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

224,352

3

181,873

2

148,559

2

69,704

3

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

224,352

4

136,405

3

111,420

3

69,704

5

C

Severe pain, severe short-term impairment, or hospitalization

299,136

6

136,405

5

111,420

5

92,938

7

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

 

n.a.

 

n.a.

 

n.a.

 

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

 

n.a.

 

n.a.

 

n.a.

 

n.a.

F

Total impairment

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

74,784

n.a.

22,734

n.a.

9,285

n.a.

29,043

n.a.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.7 Disease Burden: Pneumococcal Otitis Media

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

24,928,000

4

 

 

 

 

 

 

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

14,956,800

6

 

 

 

 

 

 

C

Severe pain, severe short-term impairment, or hospitalization

9,971,200

8

 

 

 

 

 

 

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

4,975,629

n.a.

 

n.a.

 

n.a.

 

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

497,563

n.a.

 

n.a.

 

n.a.

 

n.a.

F

Total impairment

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

99,712

n.a.

 

n.a.

 

n.a.

 

n.a.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.8 Incidence Rates and Case Fatality Rates for Pneumococcal Meningitis by Age

Age Group

Incidence Rate (per 100,000)

Case Fatality Rate (percent)

Under 5 years

33.8

55

5–14 years

4.1

50

15–59 years

5.1

65

60 years and over

14.7

95

Overall

9.5

61

TABLE D-17.9 Pneumococcal Meningitis: Distribution of Morbidity Categories by Age

 

Acute Morbidity Category (percent distribution)

Age Group

A

B

C

Under 5 years

0

5

95

5–14 years

0

5

95

15–59 years

0

5

95

60 years and over

0

5

95

Senegalese over a 10-year period and are shown in Table D-17.8. They are in agreement with incidence rates in Zaire reported by Greenwood (1984). Estimates of morbidity categories for acute disease are shown in Table D-17.9, and reflect the overwhelmingly severe nature of the disease. It is also assumed that 10 percent of survivors suffer severe permanent neurological impairment (category E) and that 30 percent suffer mild impairment. Disease burden estimates for pneumococcal meningitis are shown in Table D-17.10.

The total disease burden for S. pneumoniae derived using the assumptions described above is shown in Table D-17.11. Durations of illness are weighted averages of estimates for each condition. The predominant component in the estimates is the burden of pneumococcal pneumonia, which contributes about 95 percent of the S. pneumoniae—related deaths and disease in children under 15 years of age. The number of such deaths in Tables D-17.3 and D-17.11 is derived based on the assumption that current rates in the developing world approximate those before antibiotics in the United States. The other, much smaller components of the aggregate estimates in Table D-17.11 reflect estimates made from rates observed after the availability of

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.10 Disease Burden: Pneumococcal Meningitis

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

 

 

 

 

 

 

 

 

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

8,426

10

1,864

10

4,985

10

1,708

10

C

Severe pain, severe short-term impairment, or hospitalization

160,087

14

35,420

14

94,706

14

32,447

14

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

22,749

n.a.

5,593

n.a.

10,468

n.a.

512

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

7,583

n.a.

1,864

n.a.

3,489

n.a.

171

n.a.

F

Total impairment

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

92,682

n.a.

18,642

n.a.

64,799

n.a.

32,447

n.a.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-17.11 Disease Burden: Streptococcus pneumoniae

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

26,007,382

4

1,090,330

4

2,023,144

4

680,309

6

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

16,899,639

6

3,772,095

6

7,614,745

6

682,017

8

C

Severe pain, severe short-term impairment, or hospitalization

16,415,636

9

4,714,108

9

9,579,052

9

5,010,227

12

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

4,998,378

n.a.

5,593

n.a.

10,468

n.a.

512

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

505,146

n.a.

1,864

n.a.

3,489

n.a.

171

n.a.

F

Total impairment

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

3,687,300

n.a.

1,858,289

n.a.

1,948,669

n.a.

3,114,516

n.a.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

antibiotics. For the purposes of the discussion below and in Chapter 9, this estimated burden is termed the “preantibiotic” S. pneumoniae disease burden estimate; it does not necessarily represent an upper limit because pneumococcal pneumonia rates in developing countries may be higher than the rates assumed for calculations.

The precise extent of antibiotic availability and use in developing countries is not known, but it is significant and likely to increase by the time an improved vaccine might become available because of ARI treatment policies promulgated by the World Health Organization (1985). The committee believed that the disease burden estimates used in the central analysis comparisons should reflect this situation.

To account for the likely influence of present and future antibiotic use on the pneumococcal disease burden (particularly pneumonia deaths), the committee assumed that the total disease burden value (TDBV) that results from adopting the estimates in Table D-17.11 (13,224,522) would be reduced to half by antibiotic use (projected TDBV=6,612,261). This TDBV is used in the central analysis (Chapters 7 and 9).

Comparison of the estimates in Table D-17.11 with estimates for deaths and cases of pneumococcal pneumonia in children under 15 years of age derived by a different approach (Appendix B, Table B.6) reveals a considerable discrepancy, even when the disease burden shown in Table D-17.11 is assumed to be reduced by half from antibiotic use. While estimates shown in Table B.6 do not include pneumococcal meningitis and otitis media, calculations above suggest that these conditions would not proportionally add greatly to the pneumococcal pneumonia burden (i.e., probably less than 5 percent). The TDBV based on estimates in Table B.6 is 1,921,300. This is termed the “low” estimate for discussion purposes.

These discrepancies reflect the uncertainty of assumptions on which estimates of the true disease burden are based. To illustrate the effects of differences in assumptions about disease burden on the rankings of health benefits from vaccine candidates, analyses were conducted using the preantibiotic and low (Appendix B) estimates, as well as the projected estimate used in the central analysis. The results of this sensitivity analysis are discussed in Chapter 9.

PROBABLE VACCINE TARGET POPULATION

Persons of all ages, whether in good or impaired health, are at risk of pneumococcal infection. Attack rates of pneumococcal illness are highest at the extremes of age. Available evidence suggests that, although attack rates of pneumococcal infection in persons of the same age may not vary greatly with the state of health, mortality from such infection may be significantly higher in those whose health is compromised.

Infants and young children constitute a major target population because of the extremely high attack rate of pneumococcal otitis media in all societies. Because young children fail to respond immunologically to a number of bacterial polysaccharide antigens, vaccines with increased immunogenicity, such as polysaccharides conjugated to

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

proteins, probably will be needed to protect children from under 4 to 8 years of age.

An ideal strategy would be to immunize children with a polyvalent vaccine of conjugated pneumococcal capsular polysaccharides at about 4 to 6 months of age and, if proven desirable, a booster injection at 9 or 12 months. This program could be incorporated into the World Health Organization Expanded Program on Immunization (WHO-EPI). The protein moiety of the vaccine probably would be tetanus or diphtheria toxoid. The decision to give additional unconjugated capsular polysaccharides of types to which immunologic responsiveness is demonstrable during the first 2 years of life must await further study.

Calculations of potential vaccine benefits are based on the assumption of universal immunization of infants in developing countries.

Until universal immunization becomes routine, vaccines may be initially or additionally targeted at risk groups of other ages. Numerous studies have shown that persons of any age with one or more chronic illnesses who develop bacteremic pneumococcal infection are at significantly greater than average risk (17 percent) of a fatal outcome. This category includes persons with chronic cardiac, pulmonary, hepatic, renal, endocrine, or malignant disease; case fatality rates of treated bacteremic pneumococcal infections in these patients range from 25 to 50 percent in the United States and Europe (Austrian, 1985). For example, persons at especially high risk of death from pneumococcal bacteremia are those with anatomic or functional asplenia secondary to sickle cell anemia or thalessemia. Persons over 60 years of age also are at significantly greater risk of death. Because of these associations, the presently available 23-valent vaccine of pneumococcal capsular polysaccharides has been recommended in the United States for persons over 2 years of age with chronic illnesses or with anatomic or functional asplenia, and for individuals 65 years of age or older regardless of their state of health.

Vaccine Preventable Illness*

It is hoped that an improved vaccine for S. pneumoniae will be safe and efficacious when administered to infants, unlike the current vaccine, which is ineffective in children under 2 years of age. It is assumed that the vaccine will be administered at about 4 to 6 months of age with possibly a booster at 9 to 12 months of age.

Many studies indicate that the incidence of pneumococcal infections is highest in young children and the elderly. Although 83 pneumococcal capsular types have been identified, they differ in their propensity to cause human disease. Studies over decades in widely separated areas in

*  

Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

the United States indicate that the same 23 types account for the preponderance (more than 90 percent) of disease, although their relative frequencies vary with time and geographic area.

The WHO has established two Centres for Reference and Research on Pneumococci, one at the Statens Seruminstitut in Copenhagen, Denmark, the other at the University of Pennsylvania School of Medicine in Philadelphia. The Centres participate in world-wide surveillance of the distribution of pneumococcal capsular types isolated from blood or cerebrospinal fluid. Formulation of the currently available pneumococcal vaccine is based in part on data developed at the two Centres.

Knowledge of the distribution of agents that cause infection in any particular region is necessary before a vaccine can be formulated. This requires extensive study of isolates over a period of time, and little work of this sort has been conducted in developing countries. In a few areas, including Africa and Asia, capsular types 45 and 46 appear to cause a disproportionate amount of disease. Much additional work on the types prevalent in the developing world will be needed to achieve the possible benefits of vaccination.

It can be speculated that if predisposing factors, such as viral infections, are important in disease onset, then the viruses causing infection in children and the elderly may differ. This may affect the pneumococcal types causing disease in these age groups. Another source of uncertainty in estimating the vaccine preventable proportion of the disease burden is the duration of immunity achieved with conjugated capsular polysaccharides. Because researchers have not yet demonstrated this immunity to be as long lasting as that achieved with polysaccharides alone, infant vaccination possibly would not protect against disease in the elderly.

These uncertainties necessitate some simplifying assumptions to permit calculation of the likely benefits of a pneumococcal vaccine. For the spectrum of disease shown in Table D-17.11, the committee assumed that disease in adults and the elderly would not be prevented by infant immunization. Based on age group contributions to the TDBV, 58 percent of the disease burden falls in the under 15 years age group. Some of this burden will occur before vaccination. Hence, the committee assumed that about half of the total burden of pneumococcal illness was potentially vaccine preventable by infant immunization.

Other assumptions about the vaccine preventability of disease are plausible. Infant vaccination possibly could confer protection that would last until late in life, and thus it would not be feasible to include all capsular types causing disease in a vaccine, as assumed above. The procedures in Chapter 7 facilitate easy incorporation of alternative estimates for the vaccine preventable disease burden calculations.

SUITABILITY FOR VACCINE CONTROL

Polyvalent vaccines of pneumococcal capsular polysaccharides have been demonstrated to be safe and antigenic, and it is known that serum anticapsular antibodies, whether acquired actively or passively, provide

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

type-specific protection against infection. Despite the large number of pneumococcal capsular serotypes, most human infection is caused by a limited number of the more invasive types, which makes the production of polyvalent vaccines feasible.

Frequent administration of antibiotics to control infection has resulted in the selection of drug resistant strains in pediatric populations in several parts of the world, and multiply drug resistant strains may be difficult to control. The preponderance of deaths from pneumococcal infection in developed countries today results from irreversible physiologic injury early in the course of infection, injury unaffected by antimicrobial drugs. Prophylaxis is the only means now available for the protection of those identifiably at risk of such injury.

Alternative Control Measures and Treatments

No practical method for the long-term control of pneumococcal infection other than immunization is known. Antimicrobial prophylaxis, although feasible in special situations, has the potential risk of adverse drug reactions or drug resistance.

Although treatment with antibiotics, such as penicillin, has greatly reduced both the morbidity and mortality of established pneumococcal infections, a group of individuals remains at high risk of death. Currently, immunoprophylaxis is the sole available means for protecting such persons.

PROSPECTS FOR VACCINE DEVELOPMENT

Austrian (1984) recently published a major review of vaccination against pneumococcal infections, which includes the history of pneumococcal vaccine development and a review of the status of currently available vaccines. Therefore, the following section simply suggests the directions likely to lead toward improved vaccines.

Chemical conjugation of pneumococcal capsular antigens to proteins, such as diphtheria or tetanus toxoid, has been shown to alter their immunogenicity by converting the polysaccharide from a B-cell to a T-cell antigen. A vaccine of type 6A pneumococcal conjugated with tetanus toxoid has been tested in rhesus monkeys and in small numbers of human children and adults and is both immunogenic and safe. From these preliminary results, it is probable that similar conjugates of the polysaccharides of pneumococcal types 6B, 14, 19F, 19A, 23F and others could be developed in the next 5 to 7 years.

Several million persons have received vaccines of either whole pneumococci or of their capsular polysaccharides without permanent morbidity or a fatality. Transient local discomfort or pain, redness, induration, and swelling occur in 40 percent of adult recipients of the presently available vaccine, and up to 3 percent experience transient low-grade temperature elevations. Additional data are required to

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

establish the incidence of reactions to and the safety of conjugated capsular polysaccharides.

Accurate assessment of the efficacy of pneumococcal vaccines depends on establishing the causal role of the pneumococcus in an infection. Unfortunately, this role is usually uncertain. Assessing the efficacy of pneumococcal vaccines in preventing pneumococcal pneumonia must rest on the study of bacteremic pneumonia, for which the diagnosis is certain. Such studies will require large-scale, expensive clinical trials. Alternative modes of evaluation, such as case control studies and cohort studies (based on the design of Bolan et al., 1986), neither of which requires knowledge of the size of the vaccinated and unvaccinated populations at risk, are being used to refine efficacy assessments.

Evaluation of the efficacy of conjugated pneumococcal polysaccharide vaccines in preventing otitis media will require the routine use of tympanocentesis to establish causal diagnosis. This procedure is also therapeutic in that it drains pus from the middle ear and poses negligible risk when applied by trained hands.

REFERENCES

American Public Health Association. 1985. Pneumococcal pneumonia. Pp. 290–293 in Control of Communicable Diseases in Man, 14th edition, A.S.Beneson, ed. Washington, D.C.: American Public Health Association.

Austrian, R. 1984. Personal communication, University of Pennsylvania School of Medicine, Philadelphia, Penn.

Austrian, R. 1984. Pneumococcal infections. Pp. 257–288 in Bacterial Vaccines, R.Germanier, ed. New York: Academic Press.


Bolan, G., C.V.Broome, R.R.Facklam, B.D.Plikaytis, D.W.Fraser, and W.F.Schlech III. 1986. Pneumococcal vaccine efficacy in selected populations in the United States. Ann. Intern. Med. 104:1–6.


Cadoz, M., F.Denis, and I. Diop Mar. 1981. An epidemiological study of purulent meningitis cases admitted to hospitals in Dakar, 1970–1979 (in French). Bull. Organ. Mond. Santé 59(4):575–584.


Diop Mar, I., F.Denis, and M.Cadoz. 1979. Epidemiology of pneumococcal meningitis in Africa: Clinical aspects and serotypes (in French). Pathol. Biol. 27:543–548.


Greenwood, B.M. 1984. Selective primary health care: strategies for control of disease in the developing world. XIII. Acute bacterial meningitis. Rev. Infect. Dis. 6(3):374–389.


Health and Public Policy Committee, American College of Physicians. 1976. Pneumococcal vaccine. Ann. Intern. Med. 104:118–120.

Heffron, R. 1939. Pneumonia with Special Reference to Pneumococcus Lobar Pneumonia. New York: Commonwealth Fund. (Reprint. Cambridge, Mass.: Harvard University Press, 1979.)


Mäkalä, P.H., P.Karma, M.Sipila, J.Pukander, and M.Leinonen. 1983. Possibilities of preventing otitis media by vaccination. Scand. J. Infect. Dis. 39(suppl.):34–38.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Population Reference Bureau. 1984. World Population Data Sheet. Washington, D.C.: Population Reference Bureau.


World Health Organization. 1985. Case Management of Acute Respiratory Infections in Children in Developing Countries. WHO/RSD/85.15. Geneva: World Health Organization.

Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 357
Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 358
Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 359
Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Suggested Citation:"Appendix D-17: The Prospects for Immunizing Against Streptococcus pneumoniae." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
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Common diseases cost the developing world an enormous amount in terms of human life, health, and productivity, as well as lost economic potential. New and effective vaccines could not only improve the quality of life for millions of residents in developing countries, they could also contribute substantially to further economic development. Using data from the World Health Organization and other international agencies, this book analyzes disease burdens, pathogen descriptions, geographic distribution of diseases, probable vaccine target populations, alternative control measures and treatments, and future prospects for vaccine development. New Vaccine Development provides valuable insight into immunological and international health policy priorities.

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