Pneumococcal vaccines: history, current status, and future directions

Pneumococcal Vaccines: History, Current Status, and Future Directions Jay C. Butler, MD, Eugene D. Shapiro, MD, George M. Carlone, PhD

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and bacterial meningitis. Although effective antimicrobial drugs have reduced case fatality, the pneumococcus remains a leading global cause of morbidity and mortality. Therefore, prevention of infection by vaccination with the pneumococcal polysaccharide vaccine is recommended for persons at high risk for serious pneumococcal disease, such as the elderly and individuals with certain underlying medical conditions. Pneumococcal polysaccharide vaccines are safe and effective for the prevention of invasive infection among immunocompetent children and adults but are not immunogenic in infants. Conjugation of pneumococcal polysaccharides to a carrier protein improves immune responses among infants, and conjugate vaccines are currently being evaluated in large efficacy trials. The role of pneumococcal conjugate vaccines in adults has not been determined. Pneumococcal vaccines directed against pneumococcal proteins and DNA vaccines that induce antipneumococcal antibodies have been evaluated in animal models and may someday provide complementary or alternative methods for preventing pneumococcal infection. Improved utilization of the pneumococcal polysaccharide vaccine and continued development of improved vaccines are essential, and the emergence of drug-resistant strains of S. pneumoniae highlights the importance of preventing pneumococcal infections by vaccination. Am J Med. 1999;107(1A):69S–76S. © 1999 by Excerpta Medica, Inc.

From the Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (JCB, GMC), USA; and the Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut (EDS), USA. Requests for reprints should be addressed to Jay C. Butler, MD, Centers for Disease Control and Prevention, Arctic Investigations Program, 4055 Tudor Centre Drive, Anchorage, Alaska 99508-5902. © 1999 by Excerpta Medica, Inc. All rights reserved.

A BRIEF HISTORY OF PNEUMOCOCCAL VACCINES During the past 2 centuries, few infectious pathogens have matched the global impact of Streptococcus pneumoniae in terms of illness and death. The pneumococcus remains the leading cause of community-acquired pneumonia, and with markedly declining rates of Haemophilus influenzae type b (Hib) infections, S. pneumoniae is now the leading cause of bacterial meningitis in the United States.1,2 Before the availability of antimicrobial drugs, ⬎70% of patients hospitalized with pneumococcal bacteremia died.3,4 In 1911, Wright et al5 developed a crude whole-cell pneumococcal vaccine to immunize South African gold miners, a group with an extremely high incidence of serious pneumococcal infections.6 Subsequently, a number of other investigators conducted clinical trials on the safety and efficacy of polysaccharide vaccines against pneumococci of various serotypes.7–9 The validity of the results of many of these trials was questionable because of methodologic flaws, such as the lack of randomization and inadequate clinical follow-up of subjects. However, controlled trials of bivalent, trivalent, and quadrivalent polysaccharide vaccines conducted in the 1940s provided stronger evidence that these vaccines were efficacious.10,11 Two hexavalent vaccines were later commercially produced and marketed. At about the same time, antimicrobials effective against pneumococci became available, and the outcomes of patients with pneumococcal infections improved substantially. The seemingly miraculous efficacy of penicillin led to the widespread belief that pneumococcal infections were entirely curable, and clinicians, researchers, and public health officials lost interest in the prevention of this previously feared pathogen. By the 1950s, the pneumococcal vaccines had been withdrawn from the market, but by 1964, complacency over pneumococcal disease ended when Robert Austrian and Jerome Gold12 presented clinical descriptions of some 2,000 cases of pneumococcal pneumonia diagnosed at Kings County Hospital in Brooklyn between 1952 and 1962. Despite the substantial impact of antimicrobial drugs on reducing mortality, nearly 1 in 4 patients admitted with pneumococcal bacteremia died. Mortality was highest among the elderly, and nearly half of the patients 60 years of age and older who had bacteremia died. Deaths also were more common among persons with certain chronic medical conditions. Accordingly, Austrian 0002-9343/99/$20.00 69S PII S0002-9343(99)00105-9

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and others worked together to redevelop an effective polyvalent pneumococcal polysaccharide vaccine.13 To evaluate the vaccine expeditiously and at a relatively low cost, double-blind randomized controlled trials were conducted in a population with a high rate of pneumococcal infections.14 As in earlier decades, young goldminers in South Africa were recruited. These well-designed trials produced conclusive evidence of the efficacy of these vaccines for preventing invasive infection and pneumonia in this population. The estimates of protective efficacy were 76%–92%.15,16 These findings led to licensure of a 14-valent polysaccharide vaccine in the United States in 1977 that was replaced by a 23-valent vaccine in 1983.

PNEUMOCOCCAL POLYSACCHARIDE VACCINES Currently available pneumococcal vaccines, manufactured by Merck and Company (Pneumovax 23; West Point, Pennsylvania) and Lederle Laboratories (Pnu-Immune 23; Wayne, New Jersey), contain 25 ␮g of each of 23 purified capsular polysaccharide antigens of S. pneumoniae (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). Based on data from surveillance conducted by the Centers for Disease Control and Prevention (CDC), these 23 capsular types represent at least 85%–90% of the serotypes that cause invasive pneumococcal infections among children and adults in the United States, and protection also may be provided against additional serotypes that are serologically related to types in the vaccine (e.g., serotype 6A). Pneumococcal capsular polysaccharide antigens induce serotype-specific antibodies that enhance opsonization, complement-dependent phagocytosis, and killing of pneumococci by leukocytes and other phagocytic cells. Concentrations of antibodies to pneumococcal polysaccharides, as measured by radioimmunoassay or enzymelinked immunosorbent assay, begin to increase within 1 week after vaccination, and for most vaccine antigens, they remain elevated above prevaccination levels for over 5 years in healthy adults.17–19 Antibody concentrations decline more rapidly in some groups, such as the elderly and persons with certain underlying illnesses.20 –25 Immune responses may not be consistent among all 23 serotypes in the vaccine, and the magnitude of responses among vaccinees varies widely.26 Genetic factors may play an important role in the response to polysaccharide antigens. In one family, responsiveness to pneumococcal capsular polysaccharides was inherited in a mixed, codominant fashion.27 The levels of antibodies that correlate with protection against pneumococcal disease have not been clearly defined. Moreover, quantitative measurements of antibodies do not take into consideration 70S July 26, 1999 THE AMERICAN JOURNAL OF MEDICINE威

the functional activity of the antibody produced. Laboratory methods assessing functional immune responses to vaccination, such as opsonophagocytic activity and antibody avidity for pneumococcal antigens, may prove to be a better way to predict protection and may be more clinically relevant than are quantitative antibody measurements.28,29 Postlicensure epidemiologic studies have documented the vaccine’s efficacy in preventing invasive pneumococcal disease among the elderly and individuals with certain chronic medical conditions (Table 1).30 –34 Only one case-control study failed to demonstrate effectiveness against bacteremic disease,35 possibly because of study limitations such as small sample size and incomplete ascertainment of patients’ vaccination status. Additionally, the severity of underlying medical conditions of case patients may not have been comparable to that of the controls, creating a potentially biased underestimate of vaccine effectiveness. The overall efficacy against invasive pneumococcal disease among immunocompetent persons 65 years of age and older is 75%33; however, efficacy appears to decrease with advancing age.32 Although substantial antibody responses may occur even among persons 85 years and older, reduced effectiveness may be due to functional differences in antibodies produced by individuals in this age group compared with younger vaccinees.36 Nonetheless, a recent analysis of cost-effectiveness based on the efficacy of the polysaccharide vaccine for prevention of invasive infection in the elderly showed that vaccination of persons 65 years and older is costsaving.37 Only a small number of preventive health interventions have been shown to be cost saving (e.g., immunization against certain childhood infections and vaccination of the elderly against influenza). Thus, pneumococcal vaccination compares very favorably with other preventive health measures commonly used in modern medical practice. Despite the demonstrated benefits of vaccination, the pneumococcal polysaccharide vaccine is underutilized. In the 1995 Behavioral Risk Factor Surveillance System (BRFSS), only 35% of elderly US citizens reported ever having received a pneumococcal vaccine.38 These data indicate that in the United States, nearly 20 million persons 65 years and older who have never been vaccinated are at risk for serious pneumococcal infection. Moreover, African Americans, who are at greater risk of infection,39,40 were only half as likely as other US citizens to report having received the pneumococcal vaccine. The proportion of African Americans who reported receiving the vaccine actually decreased by 5.3% between 1993 and 1995. Clearly, education and vaccine delivery programs targeting those at greatest risk for disease and for underimmunization are essential. In recent years, prevention of pneumococcal infection by vaccination has become in-

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Table 1. Postlicensure Epidemiologic Studies of Pneumococcal Polysaccharide Vaccine Effectiveness Study Shapiro and Clemens, 198430 Forrester et al, 198735 Sims et al, 198831 Shapiro et al, 199132

Design Case-control Case-control Indirect cohort‡ Case-control Case-control

Indirect cohort‡

Butler et al, 199333

Farr et al, 199534

Indirect cohort‡

Case-control

Type of Pneumococcal Infection Invasive infection† Bacteremia Bacteremia Invasive infection† Invasive infection† All patients Immunocompromised§ Immunocompetent㛳 Age 65–74 yr Invasive infection† All patients Immunocompromised§ Immunocompetent㛳 Bacteremia and/or meningitis All patients Immunocompromised# Immunocompetent** Age ⱖ65 yr†† Bacteremia

Effectiveness* (%) 67 ⬍0 ⬍0 70 56 21 61 80¶ 48

95% Confidence Limits (%) 13, 87 ⬍0, 35 ⬍0, 55 37, 86 42, 76 ⬍0, 60 47, 72 51, 92 3, 72

⬍0 62

⬍0, 64 24, 81

57 49 49 75 81

45, 66 22, 67 23, 65 57, 85 34, 94

* For prevention of infection due to pneumococcal serotypes included in vaccine. † Streptococcus pneumoniae recovered from normally sterile body site. ‡ Effectiveness based on comparison of the prevalence of serotypes included in the vaccine among vaccinated and unvaccinated patients with pneumococcal infection. § Includes patients with anatomic or functional asplenia, dysgammaglobulinemia, hematologic malignancy, metastatic cancer, or systemic lupus erythematosus. 㛳 Includes patients with chronic pulmonary disease, alcoholism, diabetes mellitus, chronic renal failure, or congestive heart failure, and persons ⱖ55 years old without underlying illness. ¶ Efficacy during the first 3 years after vaccination. # Includes patients with sickle cell disease, anatomic asplenia, dysgammaglobulinemia, hematologic malignancy, chronic renal failure, nephrotic syndrome, history of organ transplant, or systemic lupus erythematosus. ** Includes patients with chronic obstructive pulmonary disease, asthma, alcoholism, diabetes mellitus, coronary vascular disease, congestive heart failure, or cirrhosis, and persons ⱖ65 years old without underlying illness. †† Includes patients ⱖ65 years old with coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, asthma, diabetes mellitus, or no underlying illness.

creasingly important in light of the emergence and spread of drug-resistant strains of pneumococci.40,41 Clinical and epidemiologic studies have identified factors associated with high risk for pneumococcal infection or death from pneumococcal disease,12,42,43 and persons with these conditions are specifically targeted for vaccination. The CDC’s Advisory Committee on Immunization Practices recommends administering the 23-valent pneumococcal polysaccharide vaccine to persons at greatest risk of serious pneumococcal infection: those who are 65 years of age and older and those who are 2 years and older who face increased risk for invasive pneumococcal disease due to chronic medical conditions (Table 2).43 One-time revaccination with pneumococcal vaccine is recommended at least 5 years after initial immunization for those at highest risk for pneumococcal infection and those most likely to experience rapid decreases in antibody levels. In addition, patients vacci-

nated before age 65 should receive a second dose at age 65 or later, provided 5 or more years have passed since the first dose (Figure 1). Localized reactions at the injection site (redness, tenderness) are more common among adults who are revaccinated 5 years or more after the primary vaccination, compared with those receiving their first vaccination, but these reactions are generally mild, self-limited, and localized.44 Severe reactions to revaccination are quite rare when 5 years or more have passed since the first dose was administered. An evaluation of 1,000 elderly Medicare enrollees who received a second dose of pneumococcal vaccine indicated that they were not significantly more likely to be hospitalized during the 30 days after vaccination than were 66,000 who received their first dose of vaccine.45 Innovative strategies to improve the protection provided by the pneumococcal polysaccharide vaccine have been proposed and are under evaluation. Vaccination of

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Table 2. Recommendations of the CDC Advisory Committee for Immunization Practices for Use of Pneumococcal Vaccine43 Indications for Vaccination

Recommendations for Revaccination

Immunocompetent patients Aged ⱖ65 yrs

Second dose recommended if patients received vaccine ⱖ5 yr previously and were ⬍65 yr at the time of vaccination

Aged 2–64 yr With congestive heart failure or cardiomyopathy With chronic obstructive pulmonary disease With diabetes mellitus With alcoholism or chronic liver disease including cirrhosis With cerebrospinal fluid leaks With functional or anatomic asplenia Living in special environments or social settings (e.g., Alaskan Natives and certain American Indian populations) Immunocompromised patients (2–64 yr) with HIV infection Leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, or generalized malignancy Chronic renal failure or nephrotic syndrome Immunosuppressive therapy including steroids Organ or bone marrow transplant

Not recommended Not recommended Not recommended Not recommended Not recommended If patient age ⬎10 yr, single revaccination ⱖ5 yr after previous dose Not recommended Single revaccination if ⱖ5 yr elapsed since first dose Single revaccination if ⱖ5 yr elapsed since first dose Single revaccination if ⱖ5 yr elapsed since first dose Single revaccination if ⱖ5 yr elapsed since first dose Single revaccination if ⱖ5 yr elapsed since first dose

HIV ⫽ human immunodeficiency virus.

Figure 1. Recommendations of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention on vaccinating persons 65 years and older against Streptococcus pneumoniae. Revaccination is not recommended for anyone who received a dose of pneumococcal vaccine at age 65 or over.

pregnant women could serve as a means of protecting infants by inducing transplacental passage of anticapsular antibodies. Infants of women in Gambia, Africa, who were vaccinated with the 23-valent polysaccharide vaccine during the third trimester of pregnancy had pneumococcal antibody concentrations that were higher at 72S July 26, 1999 THE AMERICAN JOURNAL OF MEDICINE威

birth compared with those of control infants.46 However, the safety and efficacy of maternal pneumococcal vaccination have not yet been determined. Studies conducted in animals suggest that incorporation of adjuvants into vaccine preparations may improve immune responses to the pneumococcal polysaccharide vaccine.47– 49 This ap-

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proach is particularly attractive in view of the potential for improving vaccine efficacy among immunocompromised persons and the very elderly.

CONJUGATE PNEUMOCOCCAL VACCINES Rates of invasive S. pneumoniae infection are highest during the first 2 years of life. Unfortunately, pneumococcal capsular polysaccharides are T-cell–independent antigens that induce limited antibody responses in children under 2 years. Clinical trials of pneumococcal capsular polysaccharide vaccines among young children have demonstrated limited efficacy or no evidence of efficacy, and for many of the serotypes that most commonly cause disease in the young (6A, 14, 19F, and 23F), immune responses are poor in children under 5 years.50 –52 By conjugating polysaccharide antigens to a carrier protein, the immunologic responses elicited become T-cell– dependent and induce higher antibody concentrations in infants. Additionally, memory B cells are produced and primed for booster responses—rapid and dramatic increases in antibody concentrations with subsequent doses of vaccine. This strategy has led to the development of Hib conjugate vaccines that are safe and effective in children under 2 years. The use of conjugate Hib vaccines has been accompanied by a dramatic reduction in the incidence of invasive Hib infections and carriage of the organism in children. Conjugation of pneumococcal polysaccharide antigens to a carrier protein may provide the means for preventing invasive S. pneumoniae infections during early childhood. An obstacle to this approach is the existence of 90 serotypes of S. pneumoniae.53 Currently, it does not appear possible to include more than a limited number of antigens in a conjugated formulation,54 and vaccinated individuals would remain susceptible to serotypes not included in the vaccine. Most conjugate pneumococcal vaccines under evaluation contain capsular polysaccharides of seven to 11 serotypes.54 –56 A conjugate vaccine that is effective against the seven most common serotypes in the United States (4, 14, 6B, 19F, 18C, 23F, and 9V), and against serologically cross-reactive serotypes, could prevent 86% of bacteremia cases and 83% of meningitis cases among children under 6 years.57 However, substantial differences exist in the serotypes of pneumococci that commonly cause invasive infections in other countries.58 Consequently, a heptavalent vaccine based on the most prevalent serotypes among children in one country may not be appropriate for children in a different region of the world. Moreover, these seven pneumococcal serotypes account for only 50% of the cerebrospinal fluid and blood isolates among older children and adults in the United States.57 Results from phase I and II studies demonstrate that

pneumococcal conjugate vaccines are safe and induce primary and booster antibody responses in infants and young children.55,59 – 61 Preliminary data from a large randomized trial among infants enrolled in a northern California health maintenance plan show that a heptavalent pneumococcal conjugate vaccine was highly effective for preventing invasive pneumococcal disease.62 Other randomized trials assessing the efficacy of conjugate vaccines against invasive infection and acute otitis media in infants are ongoing. A conjugate pneumococcal vaccine will likely be licensed and available during the year 2000. The role of conjugate vaccines among adults remains to be determined. Preliminary data indicate that in healthy persons 50 years and older and in patients vaccinated after treatment for Hodgkin’s disease, antibody responses to pneumococcal conjugate vaccines have not been substantially better than responses to the polysaccharide vaccine.63,64 In one study, localized reactions (pain, stiffness, and induration at the injection site) were more common among those who received the conjugate vaccine, although these symptoms were generally mild.63 One potential approach to the use of conjugate vaccines in adults is to administer conjugate vaccine to prime the immune system and then give a subsequent dose of 23valent polysaccharide vaccine to induce a booster response to the serotypes in both vaccines, as well as primary T-cell–independent responses to the serotypes in the 23-valent vaccine alone.65

FUTURE PNEUMOCOCCAL VACCINE FORMULATIONS Recent advances in biotechnology afford unprecedented opportunities to develop, produce, and deliver new vaccine formulations. A promising complementary or alternative approach for prevention of pneumococcal infections is to develop vaccines directed against noncapsular antigens common to all pneumococcal serotypes. Candidate antigens include a number of pneumococcal proteins: neuraminidase, autolysin, pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface adhesin A (PsaA or 37-kDa protein).66 – 69 These proteins could not only provide protection against all pneumococcal serotypes but would also induce a T-cell– dependent response with immunologic memory. To date, only pneumolysin, PspA, and PsaA have been extensively examined for suitability as vaccine candidates, and no large trials in humans have been conducted. Intranasal immunization of mice with PspA induced mucosal and systemic antibody responses, prevented pneumococcal colonization, and provided protection against systemic infection after intravenous, intratracheal, and intraperitoneal challenge.70 An innovative approach to immunization involves in-

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troduction of a DNA plasmid carrying a protein-coding gene. The plasmid transfects host cells and leads to expression of an antigen that elicits an immune response. Such immunizing agents, colloquially known as “DNA vaccines,” could be manufactured more easily and may be more stable during storage and distribution than vaccines composed of inactivated or attenuated microorganism, subcellular fractions, or recombinant protein.71 Results of preliminary work on a pneumococcal DNA vaccine are promising. Immunization of mice with a plasmid expressing PspA has been shown to induce a significant immune response and provide some protection against a challenge with intravenously administered serotype 3 S. pneumoniae.72

CONCLUSION

11.

12.

13.

14.

Despite effective antimicrobial drugs and modern intensive care support, S. pneumoniae continues to be a leading cause of morbidity and mortality. The pioneering work of Robert Austrian has led to pneumococcal polysaccharide vaccines that are effective for preventing life-threatening pneumococcal infections. Overcoming obstacles to immunization of high-risk patients and continuing to develop effective vaccines for everyone at increased risk, particularly infants and the immunocompromised, are major goals in the effort to conquer this fascinating and often deadly pathogen. The recent emergence of drugresistant strains of S. pneumoniae increases the urgency of preventing pneumococcal infections by vaccination.

REFERENCES 1. Marston BJ, Plouffe JF, File TM, et al. Incidence of community-acquired pneumonia requiring hospitalization: results of population-based active surveillance in Ohio. Arch Intern Med. 1997;157:1709 –1718. 2. Schuchat A, Deaver-Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. N Engl J Med. 1997;337:970 –976. 3. Sutliff WD, Finland M. Type 1 pneumococcal infections with especial reference to specific serum treatment. N Engl J Med. 1934;210:237–245. 4. Tilghman RC, Finland M. Clinical significance of bacteremia in pneumococcal pneumonia. Arch Intern Med. 1937;59: 602– 619. 5. Wright AE, Morgan W, Colbrook L, Dodgson RW. Observations on prophylactic inoculations against pneumococcus infection, and on the results which have been achieved by it. Lancet. 1914;1:1–10, 87–95. 6. Maynard GD. An enquiry into the etiology, manifestations and prevention of pneumonia amongst natives on the Rand from tropical areas. Publ S Afr Inst Med Res. 1913;1:1–101. 7. Lister FS. Prophylactic inoculation of man against pneumococcal infections, and more particularly against lobar pneumonia. Publ S Afr Inst Med Res. 1917;10:304 –322. 8. Ekwurzel GM, Simmons JS, Dublin H, Felton LD. Studies of immunizing substances in pneumococci. VIII. Report on field test to determine the prophylactic value of a pneumococcus antigen. Public Health Rep. 1938;53:1877–1893. 9. Felton LD. Studies on immunizing substances in pneumo74S July 26, 1999 THE AMERICAN JOURNAL OF MEDICINE威

10.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

cocci. VII. Response in human beings to antigenic pneumococcus polysaccharides, type I and II. Public Health Rep. 1938;53:2855–2877. MacLeod CM, Hodges RG, Heidelberger M, Bernhard WG. Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J Exp Med. 1945; 82:445– 465. Kaufman P. Pneumonia in old age, active immunization against pneumonia with pneumococcus polysaccharides; results of a six year study. Arch Intern Med. 1947;79:518 – 531. Austrian R, Gold J. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med. 1964;60:759 –776. U.S. Congress, Office of Technology Assessment. A Review of Selected Federal Vaccine and Immunization Policies. Washington, DC: U.S. Government Printing Office, 1979. Austrian R. A reassessment of pneumococcal vaccine. N Engl J Med. 1984;310:651– 653. Austrian R, Douglas RM, Schiffman G, et al. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians. 1976;89:184 –189. Smit P, Oberholzer D, Hayden-Smith S, Koornhof HJ, Hilleman MR. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA. 1977;238:2613–2616. 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 –275. Mufson MA, Krause BE, Schiffman G, Hughey DF. Pneumococcal antibody levels one decade after immunization of healthy adults. Am J Med Sci. 1987;293:279 –284. Musher DM, Groover JE, Rowland JM, et al. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis. 1993;17:66 –73. Vella PP, McLean AA, Woodhour AF, Weibel RE, Hilleman MR. Persistence of pneumococcal antibodies in human subjects following vaccination. Proc Soc Exp Biol Med. 1980;164:435– 438. Hilleman MR, Carlson AJ, McLean AA, Vella PP, Weibel RE, Woodhour AF. Streptococcus pneumoniae polysaccharide vaccine: age and dose responses, safety, persistence of antibody, revaccination, and simultaneous administration of pneumococcal and influenza vaccines. Rev Infect Dis. 1981;3(suppl):S31–S42. Kraus C, Fischer S, Ansorg R, Hu¨ttemann U. Pneumococcal antibodies (IgG, IgM) in patients with chronic obstructive lung disease 3 years after pneumococcal vaccination. Med Microbiol Immunol. 1985;174:51–58. Minor DR, Schiffman G, McIntosh LS. Response of patients with Hodgkin’s disease to pneumococcal vaccine. Ann Intern Med. 1979;90:887– 892. Schmid GP, Smith RP, Baltch AL, Hall CA, Schiffman G. Antibody response to pneumococcal vaccine in patients with multiple myeloma. J Infect Dis. 1981;143:590 –597. Sankilampi U, Honkanen PO, Bloigu A, Leinonen M. Persistence of antibodies to pneumococcal capsular polysaccharide vaccine in the elderly. J Infect Dis. 1997;176:1100 – 1104. Go ES, Ballas ZK. Anti-pneumococcal antibody response in normal subjects: a meta-analysis. J Allergy Clin Immunol. 1996;98:205–215. Musher DM, Groover JE, Watson DA, et al. Genetic regu-

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28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42. 43.

lation of the capacity to make immunoglobulin G to pneumococcal capsular polysaccharides. J Invest Med. 1997; 45:57– 68. Romero-Steiner S, Libutti D, Pais LB, et al. Standardization of an opsonophagocytic assay of the measurement of functional antibody activity against Streptococcus pneumoniae using differentiated HL-60 cells. Clin Diagn Lab Immunol. 1997;4:415– 422. Wenger JD, Steiner SR, Pais LB, et al. Laboratory correlates for protective efficacy of pneumococcal vaccines: How can they be identified and validated? (Abstract G-37.) 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, Louisiana, 1996:150. 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;101:325–330. 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– 657. Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med. 1991;325:1453–1460. Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Polysaccharide pneumococcal vaccine efficacy: an evaluation of current recommendations. JAMA. 1993;270:1826 –1831. Farr BM, Johnston BL, Cobb DK, et al. Preventing pneumococcal bacteremia in patients at risk. Results of a matched case-control study. Arch Intern Med. 1995;155: 2336 –2340. Forrester BL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med. 1987;83:425– 430. Romero-Steiner S, Pais LB, Groover J, et al. Evaluation of functional antibody responses in elderly and middle aged vaccinees to the 23-valent pneumococcal polysaccharide vaccine. (Abstr. E-64.) 97th General Meeting of the American Society for Microbiology, Miami Beach, Florida. 1997: 251. Sisk JE, Moskowitz AJ, Whang W, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA. 1997;278:1333–1339. Centers for Disease Control and Prevention. Pneumococcal and influenza vaccination levels among adults aged ⱖ65 years. United States, 1995. MMWR. 1997;46:913–919. Bennett M, Buffington J, LaForce FM. Pneumococcal bacteremia in Monroe County, New York. Am J Public Health. 1992;82:1513–1516. Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med. 1995;333:481– 486. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention’s Pneumococcal Sentinel Surveillance System. J Infect Dis. 1996;174:986 –993. Mufson MA. Pneumococcal infections. JAMA. 1981;246: 1942–1948. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1997;46:1–24.

44. Jackson LA, Sneller V-P, Kvartskhava T, et al. Safety of revaccination with pneumococcal polysaccharide vaccine. JAMA. 1999;281:243–248. 45. Snow R, Babish JD, McBean AM. Is there any connection between a second pneumonia shot and hospitalization among Medicare beneficiaries? Pub Health Rep. 1995;110: 720 –725. 46. O’Dempsey, McArdle T, Ceesay SJ, et al. Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy. Vaccine. 1996;14:963–970. 47. Yin JZ, Bell MK, Thorbecke GJ. Effect of various adjuvants on the antibody response of mice to pneumococcal polysaccharides. J Biol Response Modif. 1989;8:190 –205. 48. Garg M, Subbarao B. Immune responses of systemic and mucosal lymphoid organs to Pnu-Immune vaccine as a function of age and the efficacy of monophosphoryl lipid A as an adjuvant. Infect Immun. 1992;60:2329 –2336. 49. Nohria A, Rubin RH. Cytokines as potential vaccine adjuvants. Biotherapy. 1994;7:261–269. 50. 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;148:131–137. 51. Koskela M, Leinonen K, Ha¨iva¨ VK, Timonen M, Ma¨kela¨ PH. First and second dose antibody responses to pneumococcal polysaccharide vaccine in infants. Pediatr Infect Dis. 1986;5:45–50. 52. Leinonen M, Sa¨kkinen A, Kalliokoski R, Luotonen J, Timonen M, Ma¨kela¨ PH. Antibody response to 14-valent pneumococcal capsular polysaccharide vaccine in preschool age children. Pediatr Infect Dis. 1986;5:39 – 44. 53. Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol. 1995;33:2759 –2762. 54. Siber GR. Pneumococcal disease: prospects for a new generation of vaccines. Science. 1994;265:1385–1387. 55. Anderson EL, Kennedy DJ, Geldmacher KM, Donnelly J, Mendelman PM. Immunogenicity of heptavalent pneumococcal conjugate vaccine in infants. J Pediatr. 1996;128: 649 – 653. 56. Dagan R, Melamed R, Muallem M, et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect Dis. 1996;174:1271–1278. 57. Butler JC, Breiman RF, Lipman BB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978 –1994: implications for development of a conjugate vaccine. J Infect Dis. 1995;171;885– 889. 58. Sniadack DH, Schwartz B, Lipman H, et al. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children: implications for vaccine strategies. Pediatr Infect Dis J. 1995;14:503–510. 59. Steinhoff MC, Edwards K, Keyserling H, et al. A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics. Pediatr Infect Dis J. 1994;13:368 –372. 60. Ka¨yhty H, Ahman H, Ro¨nnberg P-R, Tillikainen, Eskola J. Pneumococcal polysaccharide meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J Infect Dis. 1995;172:1273–1278. 61. Leach A, Ceesay SJ, Banya WA, Greenwood BM. Pilot trial of a pentavalent pneumococcal polysaccharide/protein

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conjugate vaccine in Gambian infants. Pediatr Infect Dis J. 1996;15:333–339. Black S, Shinefield H, Ray P, et al. Efficacy of heptavalent conjugate pneumococcal vaccine (Wyeth Lederle) in 37,000 infants and children: results of The Northern California Kaiser Permanente Efficacy Trial. (Abstract LB-9.) 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California, 1998:23 (program addendum). Powers DC, Anderson EL, Lottenbach K, Mink CM. Reactogenicity and immunogenicity of a protein-conjugated pneumococcal oligosaccharide vaccine in older adults. J Infect Dis. 1996;173:1014 –1018. Molrine DC, George S, Tarbell N, et al. Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin’s disease. Ann Intern Med. 1995;123:828 – 834. Chan CY, Molrine DC, George S, et al. Pneumococcal conjugate vaccine primes for antibody responses to polysaccharide pneumococcal vaccines after treatment of Hodgkin’s disease. J Infect Dis. 1996;173:256 –258. Lock RA, Paton JC, Hansman D. Comparative efficacy of pneumococcal neuraminidase and pneumolysin as immunogens protective against Streptococcus pneumoniae. Microb Pathog. 1988;5:461– 467.

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67. McDaniel LS, Sheffield JS, Delucchi P, Briles DE. PspA, a surface protein of Streptococcus pneumoniae, is capable of eliciting protection against pneumococci of more than one capsular serotype. Infect Immun. 1991; 59:222–228. 68. Sampson JS, Furlow Z, Whitney AM, Williams D, Facklam R, Carlone GM. Limited diversity of Streptococcus pneumoniae psaA among pneumococcal vaccine serotypes. Infect Immun. 1997;65:1967–1971. 69. Paton JC, Andrew PW, Boulnois GJ, Mitchell TJ. Molecular analysis of the pathogenicity of Streptococcus pneumoniae: the role of pneumococcal proteins. Annu Rev Microbiol. 1993;47:89 –115. 70. Wu H-Y, Nahm NK Guo Y, Russell MW, Briles DE. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage, pulmonary infection, and sepsis with Streptococcus pneumoniae. J Infect Dis. 1997;175:839 – 846. 71. Whalen RG. DNA vaccines for emerging infectious diseases: what if? Emerging Infect Dis. 1996;2:168 –175. 72. McDaniel LS, Loechel F, Benedict C, et al. Immunization with a plasmid expressing pneumococcal surface protein A (PspA) can elicit protection against fatal infection with Streptococcus pneumoniae. Gene Ther. 1997;4:375–377.

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