Recommendations of the Immunization Practices Advisory Committee Pneumococcal Polysaccharide Vaccine

These recommendations update the last statement by the Immunization Practices Advisory Committee (ACIP) on pneumococcal polysaccharide vaccine (MMWR 1984;33:273-6, 281) and include new information regarding 1) vaccine efficacy, 2) use in persons with human immunodeficiency virus (HIV) infection and in other groups at increased risk of pneumococcal disease, and 3) guidelines for revaccination.

INTRODUCTION

Disease caused by Streptococcus pneumoniae (pneumococcus) remains an important cause of morbidity and mortality in the United States, particularly in the very young, the elderly, and persons with certain high-risk conditions. Pneumococcal pneumonia accounts for 10%-25% of all pneumonias and an estimated 40,000 deaths annually (1). Although no recent data from the United States exist, in the United Kingdom pneumococcal infections may account for 34% of pneumonias in adults who require hospitalization (2). The best estimates of the incidence of serious pneumococcal disease in the United States are based on surveys and community-based studies of pneumococcal bacteremia. Recent studies suggest annual rates of bacteremia of 15-19/100,000 for all persons, 50/100,000 for persons greater than or equal to 65 years old, and 160/100,000 for children less than or equal to 2 years old (3,4). These rates are 2-3 times those previously documented in the United States. The overall rate for pneumococcal bacteremia in some Native American populations can be six times the rate of the general population (5). The incidence of pneumococcal pneumonia can be 3-5 times that of the detected rates of bacteremia. The estimated incidence of pneumococcal meningitis is 1-2/100,000 persons.

Mortality from pneumococcal disease is highest in patients with bacteremia or meningitis, patients with underlying medical conditions, and older persons. In some high-risk patients, mortality has been reported to be greater than 40% for bacteremic disease and 55% for meningitis, despite appropriate antimicrobial therapy. Over 90% of pneumococci remain very sensitive to penicillin.

In addition to the very young and persons greater than or equal to 65 years old, patients with certain chronic conditions are at increased risk of developing pneumococcal infection and severe pneumococcal illness. Patients with chronic cardiovascular diseases, chronic pulmonary disease, diabetes mellitus, alcoholism, and cirrhosis are generally immunocompetent but have increased risk. Other patients at greater risk because of decreased responsiveness to polysaccharide antigens or more rapid decline in serum antibody include those with functional or anatomic asplenia (e.g., sickle cell disease or splenectomy), Hodgkin's disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, and organ transplantation. In a recent population-based study, all persons 55-64 years old with pneumococcal bacteremia had at least one of these chronic conditions (4). Studies indicate that patients with acquired immunodeficiency syndrome (AIDS) are also at increased risk of pneumococcal disease, with an annual attack rate of pneumococcal pneumonia as high as 17.9/1000 (6-8). This observation is consistent with the B-cell dysfunction noted in patients with AIDS (9,10). Recurrent pneumococcal meningitis may occur in patients with cerebrospinal fluid leakage complicating skull fractures or neurologic procedures.

PNEUMOCOCCAL POLYSACCHARIDE VACCINE

The current pneumococcal vaccine (Pneumovax (R) 23, Merck Sharp & Dohme, and Pnu-Imune (R) 23, Lederle Laboratories) is composed of purified capsular polysaccharide antigens of 23 types of S. pneumoniae (Danish types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F). It was licensed in the United States in 1983, replacing a 14-valent vaccine licensed in 1977. Each vaccine dose (0.5 mL) contains 25 ug of each polysaccharide antigen. The 23 capsular types in the vaccine cause 88% of the bacteremic pneumococcal disease in the United States. In addition, studies of the human antibody response indicate that cross-reactivity occurs for several types (e.g., 6A and 6B) that cause an additional 8% of bacteremic disease (11).

Most healthy adults, including the elderly, show a twofold or greater rise in type-specific antibody, as measured by radioimmunoassay, within 2-3 weeks of vaccination. Similar antibody responses have been reported in patients with alcoholic cirrhosis and diabetes mellitus requiring insulin. In immunocompromised patients, the response to vaccination may be less. In children less than 2 years old, antibody response to most capsular types is generally poor. In addition, response to some important pediatric pneumococcal types (e.g., 6A and 14) is decreased in children less than 5 years old (12,13).

Following vaccination of healthy adults with polyvalent pneumococcal vaccine, antibody levels for most pneumococcal vaccine types remain elevated at least 5 years; in some persons, they fall to prevaccination levels within 10 years (14,15). A more rapid decline in antibody levels may occur in children. In children who have undergone splenectomy following trauma and in those with sickle cell disease, antibody titers for some types can fall to prevaccination levels 3-5 years after vaccination (16,17). Similar rates of decline can occur in children with nephrotic syndrome (18).

Patients with AIDS have been shown to have an impaired antibody response to pneumococcal vaccine (10,19). However, asymptomatic HIV-infected men or those with persistent generalized lymphadenopathy respond to the 23-valent pneumococcal vaccine (20).

VACCINE EFFICACY

In the 1970s, pneumococcal vaccine was shown to reduce significantly the occurrence of pneumonia in young, healthy populations in South Africa and Papua New Guinea, where incidence of pneumonia is high (21,22). It was also demonstrated to protect against systemic pneumococcal infection in hyposplenic patients in the United States (23). Since then, studies have attempted to assess vaccine efficacy in other U.S. populations (24-30; CDC, unpublished data) (Table_1). A prospective, ongoing case-control study in Connecticut has shown an overall protective efficacy of 61% against pneumococcal bacteremia caused by vaccine- and vaccine-related serotypes. The protective efficacy was 60% for patients with alcoholism or chronic pulmonary, cardiac, or renal disease and 64% for patients greater than or equal to 55 years old without other high-risk chronic conditions (25,26). In another multicenter case-control study, vaccine efficacy in immunocompetent persons greater than or equal to 55 years old was 70% (27). A smaller case-control study of veterans failed to show efficacy in preventing pneumococcal bacteremia (28), but determination of the vaccination status was judged to be inadequate and the selection of controls was considered to be potentially biased.

Studies based on CDC's pneumococcal surveillance system suggest an efficacy of 60%-64% for vaccine-type strains in patients with bacteremic disease. For all persons greater than or equal to 65 years of age (including persons with chronic heart disease, pulmonary disease, or diabetes mellitus), vaccine efficacy was 44%-61% (29; CDC, unpublished data). In addition, estimates of vaccine efficacy for serologically related types were 29%-66% (29). Limited data suggest that clinical efficacy may decline greater than or equal to 6 years after vaccination (CDC, unpublished data).

A randomized, double-blind, placebo-controlled trial among high-risk veterans showed no vaccine efficacy against pneumococcal pneumonia or bronchitis (30); however, case definitions used were judged to have uncertain specificity. In addition, this study had only a 6% ability to detect a vaccine efficacy of 65% for pneumococcal bacteremia (31). In contrast, a French clinical trial found pneumococcal vaccine to be 77% effective in reducing the incidence of pneumonia in nursing home residents (32).

Despite conflicting findings, the data continue to support the use of the pneumococcal vaccine for certain well-defined groups at risk.

RECOMMENDATIONS FOR VACCINE USE

Adults

1. Immunocompetent adults who are at increased risk of pneumococcal disease or its complications because of chronic illnesses (e.g., cardiovascular disease, pulmonary disease, diabetes mellitus, alcoholism, cirrhosis, or cerebrospinal fluid leaks) or who are greater than or equal to 65 years old.

2. Immunocompromised adults at increased risk of pneumococcal disease or its complications (e.g., persons with splenic dysfunction or anatomic asplenia, Hodgkin's disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, or conditions such as organ transplantation associated with immunosuppression).

3. Adults with asymptomatic or symptomatic HIV infection.

Children

1. Children greater than or equal to 2 years old with chronic illnesses specifically associated with increased risk of pneumococcal disease or its complications (e.g., anatomic or functional asplenia {including sickle cell disease}, nephrotic syndrome, cerebrospinal fluid leaks, and conditions associated with immunosuppression).

2. Children greater than or equal to 2 years old with asymptomatic or symptomatic HIV infection.

3. The currently available 23-valent vaccine is not indicated for patients having only recurrent upper respiratory tract disease, including otitis media and sinusitis.

Special Groups

Persons living in special environments or social settings with an identified increased risk of pneumococcal disease or its complications (e.g., certain Native American populations).

ADVERSE REACTIONS

Approximately 50% of persons given pneumococcal vaccine develop mild side effects, such as erythema and pain at the injection site. Fever, myalgia, and severe local reactions have been reported in less than 1% of those vaccinated. Severe systemic reactions, such as anaphylaxis, rarely have been reported.

PRECAUTIONS

The safety of pneumococcal vaccine for pregnant women has not been evaluated. Ideally, women at high risk of pneumococcal disease should be vaccinated before pregnancy.

TIMING OF VACCINATION

When elective splenectomy is being considered, pneumococcal vaccine should be given at least 2 weeks before the operation, if possible. Similarly, for planning cancer chemotherapy or immunosuppressive therapy, as in patients who undergo organ transplantation, the interval between vaccination and initiation of chemotherapy or immunosuppression should also be at least 2 weeks.

REVACCINATION

In one study, local reactions after revaccination in adults were more severe than after initial vaccination when the interval between vaccinations was 13 months (33) (Table_2 (p. 73)). Reports of revaccination after longer intervals in children and adults, including a large group of elderly persons revaccinated at least 4 years after primary vaccination, suggest a similar incidence of such reactions after primary vaccination and revaccination (unpublished data; 17,34-38).

Without more information, persons who received the 14-valent pneumococcal vaccine should not be routinely revaccinated with the 23-valent vaccine, as increased coverage is modest and duration of protection is not well defined. However, revaccination with the 23-valent vaccine should be strongly considered for persons who received the 14-valent vaccine if they are at highest risk of fatal pneumococcal infection (e.g., asplenic patients). Revaccination should also be considered for adults at highest risk who received the 23-valent vaccine greater than or equal to 6 years before and for those shown to have rapid decline in pneumococcal antibody levels (e.g., patients with nephrotic syndrome, renal failure, or transplant recipients). Revaccination after 3-5 years should be considered for children with nephrotic syndrome, asplenia, or sickle cell anemia who would be less than or equal to 10 years old at revaccination.

STRATEGIES FOR VACCINE DELIVERY

Recommendations for pneumococcal vaccination have been made by the ACIP, the American Academy of Pediatrics, the American College of Physicians, and the American Academy of Family Physicians. Recent analysis indicates that pneumococcal vaccination of elderly persons is cost-effective (39). The vaccine is targeted for approximately 27 million persons aged greater than or equal to 65 years and 21 million persons aged less than 65 years with high-risk conditions (1). Despite Medicare reimbursement for costs of the vaccine and its administration, which began in 1981, annual use of pneumococcal vaccine has not increased above levels observed in earlier years (40) (Figure_1). In 1985, less than 10% of the 48 million persons considered to be at increased risk of serious pneumococcal infection were estimated to have ever received pneumococcal vaccine (1).

Opportunities to vaccinate high-risk persons are missed both at time of hospital discharge and during visits to clinicians' offices. Two thirds or more of patients with serious pneumococcal disease had been hospitalized at least once within 5 years before their pneumococcal illness, yet few had received pneumococcal vaccine (40). More effective programs for vaccine delivery are needed, including offering pneumococcal vaccine in hospitals (at the time of discharge), clinicians' offices, nursing homes, and other chronic-care facilities. Many patients who receive pneumococcal vaccine should also be immunized with influenza vaccine (41), which can be given simultaneously at a different site. In contrast to pneumococcal vaccine, influenza vaccine is given annually.

VACCINE DEVELOPMENT

A more immunogenic pneumococcal vaccine preparation is needed, particularly for children less than 2 years old. The development of a protein-polysaccharide conjugate vaccine for selected capsular types holds promise.

References

1. Williams WW, Hickson MA, Kane MA, Kendal AP, Spika JS, Hinman AR. Immunization policies and vaccine coverage among adults: the risk for missed opportunities. Ann Intern Med 1988;108:616-25.

2. Research Committee of the British Thoracic Society and the Public Health Laboratory Service. Community-acquired pneumonia in adults in British hospitals in 1982-1983: a survey of aetiology, mortality, prognostic factors and outcome. Quart J Med 1987; 62:195-220.

3. Istre GR, Tarpay M, Anderson M, Pryor A, Welch D, Pneumococcus Study Group. Invasive disease due to Streptococcus pneumoniae in an area with a high rate of relative penicillin resistance. J Infect Dis 1987;156: 732-5.

4. Breiman RF, Navarro VJ, Darden PM, Darby CP, Spika JS. Streptococcus pneumoniae bacteremia in residents of Charleston County, South Carolina, a decade later (Abstract). In: Program and abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1988:343.

5. Davidson M, Schraer CD, Parkinson AJ, et al. Invasive pneumococcal disease in an Alaska Native population, 1980 through 1986. JAMA 1989; 261:715-8.

6. Polsky B, Gold JWM, Whimbey E, et al. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986;104: 38-41.

7. Simberkoff MS, Sadr WE, Schiffman G, Rahal JJ. Streptococcus pneumoniae infections and bacteremia in patients with acquired immune deficiency syndrome, with report of a pneumococcal vaccine failure. Am Rev Respir Dis 1984;130:1174-6.

8. Stover DE, White DA, Romano PA, Gellene RA, Robeson WA. Spectrum of pulmonary diseases associated with the acquired immune deficiency syndrome. Am J Med 1985; 78:429-37.

9. Lane CH, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983;309:453-8.

10. Ammann AJ, Schiffman G, Abrams D, Volberding P, Ziegler J, Conant M. B-cell immunodeficiency in acquired immune deficiency syndrome. JAMA 1984;251:1447-9.

11. Robbins JB, Austrian R, Lee C-J, et al. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983; 148:1136-59.

12. Douglas RM, Paton JC, Duncan SJ, Hansman DJ. Antibody response to pneumococcal vaccination in children younger than five years of age. J Infect Dis 1983;148:131-7.

13. Leinonen M, Sakkinen A, Kalliokoski R, Luotenen J, Timonen M, Makelda PH. Antibody response to 14-valent pneumococcal capsular polysaccharide vaccine in pre-school age children. Pediatr Infect Dis 1986;5:39-44.

14. Mufson MA, Krause HE, Schiffman G. Long-term persistence of antibody following immunization with pneumococcal polysaccharide vaccine. Proc Soc Exp Biol Med 1983; 173:270-5.

15. Mufson MA, Krause HE, Schiffman G, Hughey DF. Pneumococcal antibody levels one decade after immunization of healthy adults. Am J Med Sci 1987;293:279-84.

16. Giebink GS, Le CT, Schiffman G. Decline of serum antibody in splenectomized children after vaccination with pneumococcal capsular polysaccharides. J Pediatr 1984;105:576-84.

17. Weintrub PS, Schiffman G, Addiego JE Jr, et al. Long-term follow-up and booster immunization with polyvalent pneumococcal polysaccharide in patients with sickle cell anemia. J Pediatr 1984;105:261-3.

18. Spika JS, Halsey NA, Le CT, et al. Decline of vaccine-induced antipneumococcal antibody in children with nephrotic syndrome. Am J Kidney Dis 1986;7:466-70.

19. Ballet J-J, Sulcebe G, Couderc L-J, et al. Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy. Clin Exp Immunol 1987;68:479-87.

20. Huang K-L, Ruben FL, Rinaldo CR Jr, Kingsley L, Lyter DW, Ho M. Antibody responses after influenza and pneumococcal immunization in HIV-infected homosexual men. JAMA 1987;257:2047-50.

21. Austrian R, Douglas RM, Schiffman G, et al. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians 1976;89:184-94.

22. Riley ID, Tarr PI, Andrews M, et al. Immunisation with a polyvalent pneumococcal vaccine: reduction of adult respiratory mortality in a New Guinea Highlands community. Lancet 1977;1:1338-41.

23. Ammann AJ, Addiego J, Wara DW, Lubin B, Smith WB, Mentzer WC. Polyvalent pneumococcal-polysaccharide immunization of patients with sickle-cell anemia and patients with splenectomy. N Engl J Med 1977; 297:897-900.

24. Austrian R. Surveillance of pneumococcal infection for field trials of polyvalent pneumococcal vaccines. Bethesda, Maryland: National Institutes of Health, National Institute of Allergy and Infectious Diseases, 1980; report no. DAB-VDP-12-84.

25. Shapiro ED, Clemens JD. A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med 1984;101:325-30.

26. Shapiro ED, Austrian R, Adair RK, Clemens JD. The protective efficacy of pneumococcal vaccine (Abstract). Clin Res 1988;36:470A.

27. Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988;108:653-7.

28. Forrester HL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med 1987;83:425-30.

29. Bolan G, Broome CV, Facklam RR, Plikaytis BD, Fraser DW, Schlech WF III. Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med 1986;104:1-6.

30. Simberkoff MS, Cross AP, Al-Ibrahim M, et al. Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans Administration cooperative study. N Engl J Med 1986; 315:1318-27.

31. Shapiro ED. Pneumococcal vaccine failure (Letter). N Engl J Med 1987; 316:1272-3.

32. Gaillat J, Zmirou D, Mallaret MR, et al. Essai clinique du vaccin antipneumococcique chez des personnes agees vivant en institution. Rev Epidemiol Sante Publique 1985;33:437-44.

33. Borgono JM, McLean AA, Vella PP, et al. Vaccination and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc Soc Exper Biol Med 1978;157:148-54.

34. Carlson AJ, Davidson WL, McLean AA, et al. Pneumococcal vaccine: dose, revaccination, and coadministration with influenza vaccine. Proc Soc Exper Biol Med 1979;161:558-63.

35. Rigau-Perez JG, Overturf GD, Chan LS, Weiss J, Powars D. Reactions to booster pneumococcal vaccination in patients with sickle cell disease. Pediatr Infect Dis 1983;2:199-202.

36. Lawrence EM, Edwards KM, Schiffman G, Thompson JM, Vaughn WK, Wright PF. Pneumococcal vaccine in normal children. Am J Dis Child 1983;137: 846-50.

37. Mufson MA, Krause HE, Schiffman G. Reactivity and antibody responses of volunteers given two or three doses of pneumococcal vaccine. Proc Soc Exper Biol Med 1984;177:220-5.

38. Kaplan J, Sarnaik S, Schiffman G. Revaccination with polyvalent pneumococcal vaccine in children with sickle cell anemia. Am J Pediatr Hematol Oncol 1986;8:80-2.

39. Sisk JE, Riegelman RK. Cost effectiveness of vaccination against pneumococcal pneumonia: an update. Ann Intern Med 1986;104:79-86.

40. Fedson DS. Influenza and pneumococcal immunization strategies for physicians. Chest 1987;91:436-43.

41. ACIP. Prevention and control of influenza. MMWR 1988;37:361-4,369-73.

TABLE 1. Clinical effectiveness of pneumococcal vaccination in U.S. populations
========================================================================================================
                                                                             Vaccine
                                                                Type         efficacy
Location         Method                  No. persons         infection         (%)       95% C.I.
--------------------------------------------------------------------------------------------------
Connecticut      Case-control *        543 cases          VT +, VT-related      61        42, 73
  (25,26)                              543 controls

Philadelphia     Case control *        122 cases          All serotypes         70        37, 86
  (27)                                 244 controls

Denver           Case control *         89 cases          All serotypes        -21      -221, 55
  (28)                                  89 controls

CDC-1            Epidemiologic *       249 vaccinated     VT                    64        47, 76
  (29)                                1638 unvaccinated

CDC-2            Epidemiologic *       240 vaccinated     VT                    60        45, 70
 (unpublished)                        1527 unvaccinated

VA cooperative   Randomized           1145 vaccinated     All serotypes        -34 @    -119, 18 @
  study (30)     controlled trial &   1150 controls       VT                   -19 @    -164, 47 @
--------------------------------------------------------------------------------------------------
* Only patients with isolates from normally sterile body sites were included.
+ Vaccine-type pneumococcal infection.
& Pneumococcal pneumonia and bronchitis were diagnosed primarily by culture of respiratory secretions.
@ Values calculated from the published data.
========================================================================================================

TABLE 2. Reactions to revaccination with pneumoccal vaccine
====================================================================================================================
                             Vaccinees
                      ------------------------         Revaccination
Study                 Condition      Age         No.      period       Reactions
-----------------------------------------------------------------------------------------
Borgono, et al.       Normal         Adults       7    13 mos          Increase in
  1978 (33)                                                            local reactions

Carlson, et al.       Normal         21-62 yrs   23    12-18 mos       Increase in
  1979 (34)                                                            local reactions

Rigau-Perez, et al.   Sickle         >=3 yrs     28    28-35 mos       No increase in
  1983 (35)           cell disease                                     reactions compared
                                                                       with primary
                                                                       vaccination

Lawrence, et al.      Normal         2-5 yrs     52    35 mos          Increase in
  1983 (36)                                              (mean)        local reactions

Mufson, et al.        Normal         23-40 yrs   12    24-48 mos       No increase in
  1984 (37)                                                            reactions compared
                                                                       with primary
                                                                       vaccination

Weintrub, et al.      Sickle         10-27 yrs   17    8-9 yrs         No "serious"
  1984 (17)           cell disease                                     local reactions

Kaplan, et al.        Sickle         4-23 yrs    86    37-53 mos       Four "severe"
  1986 (38)           cell disease                                     reactions *
-----------------------------------------------------------------------------------------
* Severe reaction was defined as presence of local pain, redness, swelling, and auxiliary temperature >100 F (37.8
  C); two patients aged 21 and 23 years had temperatures of 102 F (38.9 C).
====================================================================================================================

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