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INTRODUCTION — Pneumococcal infections, including pneumonia and invasive disease such as bacteremia and meningitis, are important sources of morbidity and mortality in infants and young children, older adults (≥65 years of age), and persons with conditions that affect their ability to make antibody to capsular polysaccharides. Patients with chronic lung disease are at increased risk for pneumococcal pneumonia, and patients with conditions such as heart failure are more likely to have adverse outcomes if pneumonia occurs. Asplenia greatly increases the risk for overwhelming pneumococcal sepsis, and cerebrospinal fluid leak or a cochlear implant greatly increases the risk for meningitis. Pneumococcal vaccination is recommended for all children and for adults who have a condition that places them at increased risk for developing pneumonia or invasive pneumococcal disease or for having a serious outcome should pneumonia develop.
The highest incidence of invasive pneumococcal disease occurs in children <2 years of age, persons who have conditions that compromise antibody responses (eg, solid organ transplantation, multiple myeloma, HIV infection), and those ≥65 years of age (table 1). The highest mortality rates occur in individuals ≥65 years of age, especially in those who have significant comorbidities. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Epidemiology' and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Prognosis'.)
The indications for, immunogenicity of, and efficacy and adverse reactions associated with pneumococcal vaccination in adults will be presented here. Pneumococcal vaccination in children and specific groups of high-risk adults is discussed in detail separately. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children" and "Pneumococcal immunization in HIV-infected adults" and "Prevention of sepsis in the asplenic patient", section on 'Pneumococcal vaccine' and "Immunizations in solid organ transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in patients with cancer", section on 'Pneumococcal vaccine' and "Immunizations for patients with chronic liver disease", section on 'Pneumococcal vaccine' and "Immunizations in patients with end-stage renal disease", section on 'Pneumococcal vaccine'.)
The microbiology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of pneumococcal infections are also presented separately. (See "Microbiology and pathogenesis of Streptococcus pneumoniae" and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia" and "Pneumococcal pneumonia in adults".)
APPROACH TO VACCINATION
Available vaccines — The polysaccharide capsule of Streptococcus pneumoniae is the principal means by which this bacterium resists ingestion and killing by phagocytic cells. Antibody to capsule greatly facilitates phagocytosis and killing. Accordingly, capsular polysaccharides are the essential components of all currently available pneumococcal vaccines. More than 90 different pneumococcal capsular serotypes have been identified. Since it is not possible to include all of the serotypes in a pneumococcal vaccine, available vaccines contain capsular polysaccharides from serotypes that are most commonly implicated as causes of pneumococcal disease. (See "Microbiology and pathogenesis of Streptococcus pneumoniae", section on 'Capsule'.)
Two types of pneumococcal vaccines are approved for use in the United States:
●Pneumococcal polysaccharide vaccine (PPSV) was first marketed in the 1970s as a vaccine that contained capsular polysaccharides from 14 pneumococcal serotypes that commonly caused disease. In 1983, this vaccine was modified to include capsular polysaccharides from the 23 most commonly infecting pneumococcal serotypes and is marketed as Pneumovax 23 (PPSV23) (table 2). At present, PPSV23 contains capsular polysaccharides from pneumococci that cause about 60 percent of all pneumococcal infection in adults . PPSV is used in selected adults and children ≥2 years of age but not in infants or toddlers <2 years of age since polysaccharide antigens are poorly immunogenic in this age group.
●Pneumococcal conjugate vaccine (PCV) was initially marketed in the United States in 2000 as a 7-valent vaccine, PCV7 (Prevnar 7). In 2010, PCV7 was replaced by PCV13. This vaccine consists of capsular polysaccharides from the 13 most common pneumococcal types that cause disease, covalently linked to a nontoxic protein that is nearly identical to diphtheria toxin. The covalent linking to a protein renders the polysaccharide antigenic in infants and toddlers. PCVs with different numbers of serotypes are produced in other parts of the world and are under research in the United States (table 2). Because PCV7 is an excellent immunogen in infants and toddlers, it was adopted in the United States for universal use in this age group in 2000; since 2010, PCV13 has been recommended for infants and children in its place.
Because PCV stimulates mucosal antibody, it greatly suppresses nasal carriage of S. pneumoniae due to vaccine serotypes. Not surprisingly, therefore, widespread use of PCV7 has reduced spread of pneumococci from small children, the usual reservoir of pneumococcal carriage, to unvaccinated older children and adults, an effect that is called an indirect (or "herd") effect. In the pre-PCV era, about 65 to 70 percent of pneumococcal pneumonia in adults was caused by strains included in PCV7; by 2008 in the United States, disease due to these types had nearly disappeared from the adult population. The same kind of decline in infection of adults due to serotypes in PCV13 has begun to be apparent.
In 2012, the United States Advisory Committee on Immunization Practices (ACIP) recommended PCV13 for selected high-risk adults. In 2014, the ACIP added a recommendation of PCV13 for all adults ≥65 years of age (table 3) as well as persons >2 years of age who have conditions that place them at substantially increased risk for pneumococcal infection.
In one study, it was estimated that, in 2013, PCV13 stimulated antibody to serotypes that caused 28 to 42 percent of invasive pneumococcal disease in adults in the United States . In the United States and other countries with universal PCV immunization programs, this percentage is rapidly declining as a result of indirect immunity, with a three- to four-year lag period when compared to the effect on invasive pneumococcal disease in children .
The use of pneumococcal vaccines in infants and children is discussed in detail separately. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children".)
Indications — The 23-valent pneumococcal polysaccharide vaccine has been recommended for many years in the United States for all adults ≥65 years of age and in younger patients who have a condition that increases risk for developing pneumococcal pneumonia or invasive pneumococcal disease and/or fatal complications if such infection occurs. Risk factors for invasive pneumococcal disease and pneumococcal pneumonia are discussed in detail separately. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Risk factors for infection' and "Pneumococcal pneumonia in adults", section on 'Risk factors'.)
In 2012, the ACIP recommended sequential administration of both PCV13 and PPSV23 for individuals >19 years of age with functional or anatomic asplenia, an immunocompromising condition (eg, HIV infection), a cerebrospinal fluid leak, a cochlear implant, or advanced kidney disease . We agree with this recommendation.
In 2014, the ACIP extended its recommendation for sequential administration of both PCV13 and PPSV23 to all adults ≥65 years of age . The ACIP will reevaluate its recommendations for adults ≥65 years of age in 2018 and will revise them as needed. In contrast to the ACIP, we give only PPSV23 (but not PCV13) to otherwise healthy individuals aged ≥65 years. The rationale for this is discussed below (see 'Overview of benefits and limitations' below and 'Efficacy' below). To our knowledge, no other developed country has made an official recommendation for the routine use of PCV13 in adults ≥65 years of age, but some countries recommend its use (followed by PPSV23) for immunocompromised patients.
In 2011, the US Food and Drug Administration (FDA) approved PCV13 for use in adults ≥50 years of age , and, in 2016, they expanded the approved age range to include adults 18 to 49 years of age . It is important to note, however, that approval by the FDA is not the same as recommended use. The ACIP does not recommend PCV13 for routine use in adults <65 years of age, and we concur.
ACIP recommendations for use of one or both kinds of vaccines are summarized in the Table (table 3). Specific recommendations for pneumococcal vaccination of hematopoietic cell transplant recipients are presented separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus'.)
PPSV23 — In accordance with the ACIP, we recommend PPSV23 alone for persons aged 19 to 64 years who are at increased risk for pneumococcal infection and/or serious complications of pneumococcal infection (table 3 and algorithm 1) [4,8]. Indications for revaccination as well as recommendations for patients who should receive both PPSV23 and PCV13 are discussed below. (See 'Revaccination' below and 'PCV13 and PPSV23' below.)
Adults with the following underlying conditions who are <65 years of age should receive PPSV23 (but should not receive PCV13):
●Current cigarette smoking
●Chronic heart disease, including congestive heart failure and cardiomyopathy but excluding hypertension
●Chronic lung disease, including asthma and chronic obstructive pulmonary disease (see "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Vaccination')
●Chronic liver disease, including cirrhosis (see "Immunizations for patients with chronic liver disease")
PCV13 and PPSV23 — The ACIP states that both PCV13 and PPSV23 should be given to adults of any age who have the underlying conditions listed below and to all adults aged ≥65 years (table 3) . When possible, PCV13 should be given first, followed by PPSV23; the recommended interval between the vaccines varies by patient group (table 4). The schedule for dual vaccination is discussed below. (See 'Schedule for dual vaccination' below.)
The ACIP states that the persons who should receive both PCV13 and PPV23 include those with any of the following risk factors:
●Cerebrospinal fluid leak
●Functional or anatomic asplenia, including sickle cell disease, other hemoglobinopathies, congenital asplenia, and acquired asplenia – In the absence of antibody (most unvaccinated adults lack measurable antibody to most pneumococcal capsular polysaccharides ), the only clearance of pneumococci from the bloodstream is by the spleen. Asplenic individuals are at risk for overwhelming pneumococcal sepsis that may occur even in the absence of a focal infection such as pneumonia. (See "Clinical features and management of sepsis in the asplenic patient", section on 'Role of the spleen in host defense' and "Prevention of sepsis in the asplenic patient".)
•Congenital or acquired immunodeficiency, including B or T lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease)
•HIV infection (see "Pneumococcal immunization in HIV-infected adults", section on 'When to immunize')
•Chronic renal failure
•Iatrogenic immunosuppression, including long-term systemic glucocorticoids or radiation
•Solid organ transplant
We agree with the ACIP that adults of any age with any of the high-risk conditions listed in the bullets above should receive both PCV13 and PPSV23, although evidence of efficacy in patients with many of these conditions is meager or even absent. This population is least likely to respond to either vaccine.
The ACIP also recommends that all adults aged ≥65 years of age should receive both PCV13 and PPV23. The rationale for this is that both the incidence of pneumococcal disease and the mortality rate increase after age 50 and more sharply after age 65 (table 1) . The incidence of pneumococcal disease and the associated mortality are very low in adults under the age of 50. In contrast with the ACIP, we give only PPSV23 (but not PCV13) to otherwise healthy individuals aged ≥65 years. We do not believe that PCV13 is warranted in such individuals because it is not clear that immunizing this group with PCV13 followed by PPSV23 provides benefit beyond that derived from PPSV23 alone. An important point underlying any recommendation for vaccinating adults in most developed countries is that routine administration of PCV13 to all children <2 years produces such profound indirect ("herd") immunity that there will be little if any incremental benefit from using PCV13 in adults. This is discussed in greater detail below. (See 'Overview of benefits and limitations' below and 'Efficacy' below.)
We do, however, favor the use of both PCV13 and PPSV23 in patients ≥65 years of age who have one of the conditions for which PPSV23 is indicated before age 65 (cigarette smokers; patients with chronic heart disease, chronic lung disease, diabetes mellitus, alcoholism, or chronic liver disease). We also use both PCV13 and PPSV23 in individuals ≥65 years of age who are planning to travel to a country that does not have a universal immunization program mandating pneumococcal conjugate vaccination for all infants and toddlers.
Although the ACIP has not made a recommendation about vaccinating adults who have been diagnosed with invasive pneumococcal disease, we suggest that all survivors of invasive pneumococcal disease receive PCV13 followed by PPSV23. Even if they have not been diagnosed with one of the conditions listed above, they have proven themselves to be susceptible, and infection with one serotype does not provide protection against other serotypes.
●For immunocompromised adults or adults with or advanced kidney disease (algorithm 2), functional or anatomic asplenia (algorithm 3), a CSF leak, or a cochlear implant (algorithm 4) who are any age (including those ≥65 years of age) and who have not previously received either PCV13 or PPSV23, a single dose of PCV13 should be given, followed by a dose of PPSV23 ≥8 weeks later. If such individuals have already received PPSV23, a single dose of PCV13 should be given one year after the administration of PPSV23.
●The ACIP states that, for individuals ≥65 years of age without any of the conditions described in the previous bullet, PPSV23 should be given ≥1 year following PCV13 and at least 5 years after the most recent dose of PPSV23 (algorithm 5) . In 2015, the recommended timing for administration of PPSV23 following PCV13 administration in immunocompetent adults ≥65 years of age was changed from 6-12 months to ≥1 year to simplify the administration schedule. As noted above, we give only PPSV23 (but not PCV13) for otherwise healthy individuals ≥65 years of age; our recommendation for such individuals differs from that of the ACIP. (See 'PCV13 and PPSV23' above.)
●For patients with an indication for PCV13 who have previously received one or more doses of PPSV23 but have not received PCV13, a single dose of PCV13 should be given if at least one year has elapsed since the last PPSV23 dose was given.
●For patients <65 years of age who require revaccination with PPSV23 (eg, immunocompromised patients), the first such dose should be given at least eight weeks after PCV13 and at least 5 years after the previous dose of PPSV23 .
Specific recommendations for revaccination are discussed below. (See 'Revaccination' below.)
Administration — Both pneumococcal vaccines are administered as a 0.5 mL dose. PCV13 should be given intramuscularly, whereas PPSV23 can be given either intramuscularly or subcutaneously. Intradermal administration can cause severe local reactions and should be avoided.
Administration with other vaccines — Either formulation of pneumococcal vaccine may be given concomitantly with other vaccines [12,13]. When more than one vaccine is given, they should be administered with different syringes and at different injection sites.
Concurrent administration of either PPSV23 or PCV13 with the inactivated influenza vaccine is safe and is unlikely to reduce the effectiveness of either pneumococcal vaccine [14,15]. Some data suggest a modest suppression of immunogenicity to PCV13 if PCV13 is administered on the same day as an inactivated influenza vaccine, even though different arms were used for injection . Nevertheless, the United States Centers for Disease Control and Prevention (CDC) states that these vaccines can be coadministered .
Coadministration of PPSV23 and the herpes zoster vaccine does not alter the antibody response to PPSV23 , although such coadministration may reduce the immunogenicity of the zoster vaccine [12,16,17]. In order to avoid introducing barriers to patients' receiving indicated vaccines, the ACIP states that PPSV23 and the zoster vaccine be administered at the same visit if the patient is eligible for both vaccines [18-20]. With availability of vaccines at local pharmacies, it may not be inconvenient for people to receive two vaccines a few weeks apart; this would be ideal in patients who are highly motivated and able to have two visits to receive two different vaccines (PCV13 and influenza vaccine; PPSV23 and zoster vaccine). However, if there is any question of decreased adherence, such that only one of these vaccines might be given, we favor giving both vaccines at the same time but in different arms.
In patients who require both PPSV23 and PCV13, the two vaccines should be given at different times as outlined above. (See 'Schedule for dual vaccination' above.)
Revaccination — Some studies have raised concern that repeated vaccination with pneumococcal polysaccharide vaccines may lead to hyporesponsiveness , but this does not appear to be relevant if more than five years have passed since the previous dose [22-24]. (See 'Immunogenicity' below.)
Some data have shown that injection site reactions are more common after revaccination than after primary vaccination, but, in most studies, such reactions were not severe, were self-limited, and tended to occur when the time between vaccinations was less than five years [25-27]. (See 'Adverse reactions' below.)
For patients <65 years of age who are immunocompromised or have functional or anatomic asplenia, the ACIP recommends one single revaccination with PPSV23 ≥5 years after the first dose (algorithm 2) [4,8]. However, for asplenic individuals, some European public health agencies recommend reimmunization with PPSV23 every five years ; we agree with this approach. Recommendations for asplenic patients are presented in more detail separately. (See "Prevention of sepsis in the asplenic patient", section on 'Revaccination in children and adults'.)
The ACIP recommends that all adults aged ≥65 years receive a dose of PPSV23 even if they received this vaccine before age 65; however, a minimum interval of five years between PPSV23 doses should be maintained (algorithm 5) [4,8]. We agree with the ACIP's recommendation for revaccination with PPSV23 at or after age 65 years; however, following this dose (and in contrast to the ACIP), we also favor revaccinating older adults at 10-year intervals because immunologic responses wane in older adult patients . A caveat is that insurance companies may not provide coverage for these subsequent doses.
Revaccination with PCV13 is not recommended for any age group.
OVERVIEW OF BENEFITS AND LIMITATIONS — Preventing pneumococcal disease in older adults and those with certain underlying conditions is an important goal given the burden of disease and associated morbidity and mortality in these populations . Many (but not all) studies of the pneumococcal polysaccharide vaccine have demonstrated efficacy against invasive and noninvasive pneumococcal disease , such as bacteremia and meningitis, but both immunogenicity and efficacy are lower in older adult patients and immunocompromised hosts (the ones who are most in need of the vaccine).
The development of pneumococcal conjugate vaccines represented a major advance; the universal use of such vaccines in infants has led to dramatic reductions in the incidence of pneumococcal disease. This decline is seen both among children who are vaccinated and, because the vaccine effectively eradicates nasal colonization, also among older, unvaccinated children and adults. This phenomenon, called the indirect ("herd") effect, has resulted in a greater than 90 percent decline in pneumococcal disease due to serotypes contained in the 7-valent pneumococcal conjugate vaccine (PCV7) among older children who did not receive the vaccine, as well as among adults (figure 1) [31,32]. Many authorities credit this indirect effect for the extraordinary decline in rates of S. pneumoniae in community-acquired pneumonia (CAP) studies in the United States in recent years , an effect that appears substantially less in Europe, possibly due to variations in national pneumococcal vaccine strategies. With widespread use of the 13-valent pneumococcal conjugate vaccine (PCV13) in the United States since 2010, the same degree of decline in adult infections due to vaccine serotypes is being observed, an observation that raises serious question about the potential benefits of using PCV13 routinely in adults, despite Advisory Committee on Immunization Practices (ACIP) recommendations for its use . (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness' and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Impact of childhood vaccination' and "Impact of universal infant immunization with pneumococcal (Streptococcus pneumoniae) conjugate vaccines in the United States".)
There are few data on the efficacy of pneumococcal conjugate vaccines in specific high-risk groups, such as various immunocompromised populations. The most well-studied immunocompromised group has been HIV-infected patients in Africa. In an early study, at a time when treatment for HIV infection was not available, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) offered no protection . In a later study that immunized predominantly HIV-infected patients with PCV7, by the end of the study period, 46 percent of patients were receiving antiretroviral therapy; in this study, PCV7 was effective during the first year following vaccination . Some experts use the results of these studies to support claims that pneumococcal conjugate vaccine is more effective than pneumococcal polysaccharide vaccine in HIV-infected patients; we do not agree with that conclusion because the differences in the degree of immunocompromise in the two studies are so striking. (See "Pneumococcal immunization in HIV-infected adults", section on 'Efficacy and immunogenicity of pneumococcal vaccination'.)
The CAPiTA trial, a randomized trial that included nearly 85,000 Dutch adults ≥65 years age, compared protection against pneumococcal disease in recipients of PCV13 or placebo. This trial demonstrated 46 percent efficacy of PCV13 against vaccine-type pneumococcal pneumonia, 45 percent efficacy against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy against vaccine-type invasive pneumococcal disease . Three important points need to be made about this trial: there was no comparison with PPSV23, which, historically, has demonstrated a higher rate of protection; universal vaccination of children was not accomplished before the start of the study; and immunocompromised adults were excluded. Importantly, in this study, persons who developed an immunocompromising condition during the years of observation after they received PCV13 had no demonstrable protection from PCV13. (See 'Efficacy' below.)
The recommendation to give both PPSV23 and PCV13 to high-risk adults is far more costly than recommending PPSV23 alone. In addition, adherence to a two-vaccine regimen is likely to be poorer than adherence to a one-vaccine regimen. Despite the strength of the current ACIP recommendation, data supporting this approach are meager.
An untoward effect of the widespread use of pneumococcal conjugate vaccines has been the emergence of "replacement strains," a term used to describe nonvaccine pneumococcal serotypes that appear as colonizers of the nasopharynx and as a cause of pneumococcal disease in recipients of PCV . Reduction in nasal carriage of PCV serotypes appears to create an ecologic niche for nonvaccine serotypes . As an example, S. pneumoniae type 19A (not included in PCV7 but included in PCV13) emerged as the most common cause of pneumococcal disease in children and adults a few years after universal vaccination with PCV7 began in the United States (figure 1) [31,40]. (See "Impact of universal infant immunization with pneumococcal (Streptococcus pneumoniae) conjugate vaccines in the United States".)
A comparison of the properties of pneumococcal polysaccharide and conjugate vaccines is reviewed in the Table (table 5).
PNEUMOCOCCAL POLYSACCHARIDE VACCINES — Pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23) includes 23 purified capsular polysaccharide antigens (table 2). These serotypes were initially chosen because they represented 85 to 90 percent of the serotypes that cause invasive disease in the United States. By 2009, probably due in part to the indirect effect of the 7-valent pneumococcal conjugate vaccine (PCV7), 60 to 70 percent of cases of invasive pneumococcal disease in adults in the United States were caused by PPSV23 serotypes [1,41].
Immunogenicity — A surrogate marker of successful vaccination is appearance of antibody to capsular polysaccharides or enhanced in vitro opsonic activity of serum for type-specific pneumococci contained in the vaccine. The responses may not be consistent among all serotypes in PPSV23 and vary from one individual to another. Although important for epidemiologic studies, measuring antibody responses after vaccination is rarely performed in clinical practice; an exception is patients with primary immunodeficiencies, in whom some physicians routinely check titers. (See "Assessing the immunologic response to vaccination".)
After healthy adults >50 years of age are vaccinated with PPSV23, antibodies decline rapidly over a one- to two-year period, persisting at low levels for 10 or more years [22,25,27,38]. Despite these observations, in one report from the United States Centers for Disease Control and Prevention (CDC), efficacy of the pneumococcal polysaccharide vaccine did not decline at seven or more years after vaccination .
Revaccination with PPSV23 induces persistent functional antibody response in healthy middle-aged and older adults [23,25]. Some studies have shown an inverse association between circulating antibody concentrations just before primary vaccination or revaccination and subsequent increase, consistent with other observations suggesting that it may not be useful to revaccinate patients too soon following initial vaccination . (See 'Revaccination' above.)
Efficacy — Several case-control studies, randomized trials, and meta-analyses have shown that the pneumococcal polysaccharide vaccine (PPSV) prevents pneumococcal disease. The bulk of evidence suggests that PPSV protects against invasive pneumococcal infection (defined as pneumococcal disease with isolation of the infecting organisms from a normally sterile body site) and noninvasive pneumococcal infection . Some investigators, however, have concluded that vaccine recipients are protected against invasive but not against noninvasive (ie, nonbacteremic) pneumococcal pneumonia [29,39,43-52]. Other published studies have failed to demonstrate efficacy for preventing invasive or noninvasive disease [46,47,52-55] or for reducing mortality [30,56]. A population-based case control study showed that PPSV was 85 to 90 percent effective in preventing invasive pneumococcal disease in adults <55 years of age but that the efficacy of PPSV declined as age increased, as did the duration of any observed effect . The avidity of antibody for pneumococcal polysaccharide and, therefore, the protective effect, may diminish with age .
Possible reasons for the conflicting results include the imprecision of diagnosis of the outcomes being assessed and the relatively small number of events in studies. In general, studies with more specific endpoints (eg, otitis media with culture growing S. pneumoniae after a tympanic membrane perforation or bacteremic pneumococcal disease caused by vaccine serotypes) have been more likely to demonstrate efficacy than studies with less specific endpoints (eg, otitis media without etiologic confirmation, nonbacteremic pneumococcal pneumonia, all-cause pneumonia, or all-cause mortality) .
A 2013 systematic review and meta-analysis assessed the efficacy of PPSV for preventing invasive pneumococcal disease, all-cause pneumonia, and all-cause mortality in adults in 16 randomized trials; some of the individual meta-analyses included data from fewer than 16 trials . The following results were observed:
●PPSV substantially reduced the risk of invasive pneumococcal disease (odds ratio [OR] 0.26, 95% CI 0.14-0.45).
•Among otherwise healthy individuals in low-income countries included in one trial, there was a significant reduction in invasive pneumococcal disease (OR 0.14, 95% CI 0.03-0.61). This group is considered to be at elevated risk of pneumococcal disease due to absence of vaccine use, overcrowding, and/or other environmental factors.
•Among otherwise healthy individuals in high-income countries (many of whom were older adults), PPSV was associated with a significant reduction in invasive pneumococcal disease (OR 0.20, 95% CI 0.10-0.39).
●The benefit of PPSV for preventing invasive pneumococcal disease was more pronounced when the analysis was limited to trials that specifically assessed the incidence of disease caused by serotypes included in the vaccine (OR 0.18, 95% CI 0.10-0.31).
●PPSV was also associated with a substantial reduction in both invasive (OR 0.26, 95% CI 0.15-0.46) and noninvasive pneumococcal pneumonia (OR 0.46, 95% CI 0.25-0.84).
●There was efficacy against all-cause pneumonia among individuals in low-income countries (OR 0.54, 95% CI 0.43-0.67), presumably because S. pneumoniae remains the principal cause of pneumonia in such countries but not among individuals in high-income countries in either the general population or in adults with chronic illness (probably reflecting the declining incidence of S. pneumoniae as a cause of pneumonia in developed countries).
●PPSV did not reduce all-cause mortality.
A 2009 systematic review graded randomized trials based on statistical criteria and retained only a few in their meta-analysis. When the analysis was limited to trials of highest methodologic quality, efficacy of vaccination was not observed. However, their analysis excluded many studies that other investigators regard as acceptable and gave disproportionate weight to two studies that relied on nonstandardized serologic techniques to diagnose pneumococcal pneumonia. These serologic tests have been shown to be of questionable validity for diagnosing pneumococcal pneumonia [52-54,58].
As noted above, despite the fact that antibodies following PPSV23 administration decline over time, in a report from the CDC, efficacy of the pneumococcal polysaccharide vaccine did not decline at seven or more years after vaccination .
The immunogenicity and efficacy of PPSV23 in patients with specific risk factors is discussed in detail separately. (See "Pneumococcal immunization in HIV-infected adults", section on 'Efficacy and immunogenicity of pneumococcal vaccination' and "Immunizations in solid organ transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in patients with cancer", section on 'Pneumococcal vaccine' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus' and "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Vaccination' and "Immunizations in patients with end-stage renal disease", section on 'Pneumococcal vaccine' and "Immunizations for patients with chronic liver disease", section on 'Pneumococcal vaccine'.)
Adverse reactions — The most common adverse reactions to PPSV23 are injection site pain or tenderness (in 60 percent of vaccinees), swelling or induration (in 20 percent), and erythema (in 16 percent) . These reactions usually persist for less than 72 hours. Moderate systemic reactions (eg, fever and myalgias) and more severe local reactions (eg, local induration) occur less commonly. (See "Pneumococcal polysaccharide vaccine (23-valent): Drug information".)
Some studies have suggested that injection site reactions are more common after revaccination than after primary vaccination, but, in most studies, such reactions were mild and self-limited [25-27]. One retrospective study showed no increase in medically attended adverse events among individuals who received three or more doses of PPSV23 compared with those who received one dose .
Healthcare providers should report suspected adverse events to the Vaccine Adverse Event Reporting System (VAERS). VAERS can be contacted via the VAERS website or by telephone at 800-822-7967.
Contraindications — A severe allergic reaction (eg, anaphylaxis) to PPSV23, an exceedingly rare event, is an absolute contraindication to revaccination with PPSV23 . (See "Pneumococcal polysaccharide vaccine (23-valent): Drug information".)
PNEUMOCOCCAL CONJUGATE VACCINES — Pneumococcal protein-conjugate polysaccharide vaccines have a number of beneficial properties that polysaccharide vaccines lack (table 5). Children <2 years of age respond poorly to polysaccharide antigens. However, when a polysaccharide is covalently conjugated to a carrier protein, the resulting antigen is recognized as T cell dependent, stimulating a good serum antibody response, mucosal immunity, and immunologic memory in children (including those <2 years) and adults.
Pneumococcal conjugate vaccines induce a mucosal immune response and suppress nasopharyngeal colonization. Elimination of nasal colonization causes indirect ("herd") protection, reducing rates of disease not only in vaccinated individuals but also in those who were not vaccinated, especially siblings and playmates, but also parents and other unvaccinated adults. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness'.)
A 7-valent pneumococcal conjugate vaccine (PCV7) that contained protein-conjugated capsular polysaccharides from the seven pneumococcal serotypes that most commonly infected children was recommended for universal use in infants and toddlers in the United States beginning in 2000. This recommendation was followed by a dramatic decrease in invasive pneumococcal disease in both children and adults (figure 1). In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) that contains four additional common serotypes plus types 1 and 5 (table 2), which are of major significance in underdeveloped countries, was recommended in place of PCV7. A decline in pneumococcal disease due to the serotypes that have been added to PCV13 has already been noted. In the first half of 2012, only 29 percent of all invasive pneumococcal disease in United States adults were caused by PCV13 serotypes . Some European countries have used a 10-valent vaccine, and a 15-valent vaccine is in development.
In 2012, PCV13 began to be recommended for use in selected high-risk adults. In 2014, the United States Advisory Committee on Immunization Practices (ACIP) recommended PCV13 for all adults ≥65 years of age . We agree with the ACIP that adults of any age with a high-risk condition should receive both PCV13 and the 23-valent pneumococcal polysaccharide vaccine (PPSV23). However, in contrast to the ACIP, we give only PPSV23 (but not PCV13) to otherwise healthy individuals aged ≥65 years. Detailed recommendations are provided above. (See 'Approach to vaccination' above.)
Immunogenicity — Numerous studies in adults suggest that pneumococcal conjugate vaccines (PCVs) are at least as immunogenic as PPSV23 for the serotypes covered. A careful review of all studies published until 2011 found no definitive advantage of either vaccine . In a subsequent large study, antibody levels and opsonizing activity were greater for some but not all capsular polysaccharides one month after vaccination with PCV13 compared to vaccination with PPSV23, but, by one year, no difference was apparent .
In contrast to PPSV23, PCV7 elicits a serotype-specific memory B cell response . While, in theory, it might have seemed likely that PCVs would induce a more persistent immune response than PPSV23, studies comparing these two vaccine types show that, 12 months after vaccination, antibody activity in serum was identical in subjects who received PCV13 or PPSV23 .
Immunologic priming — Because PCVs stimulate memory B cells , it was reasonable to hypothesize that such vaccines might prime the immune system for an enhanced secondary immune response to a PPSV [39,63,64]. However, several trials failed to show that a prime-boost regimen with a pneumococcal conjugate vaccine followed by a pneumococcal polysaccharide vaccine enhances immunogenicity [65-69]. Two large studies showed that PCV13 followed one year later by PPSV23 led to higher antibody activity one month after PPSV23 administration [61,64]. In a smaller study, conjugate vaccine followed by PPSV23 booster led to better antibody levels at one month but, by six months after receipt of PPSV23, antibody levels in booster recipients had fallen to their baseline . In an open-label randomized trial, administration of the PPSV23 six months prior to PCV7 resulted in attenuated antibody concentrations compared with PCV7 alone .
After considering these data, the ACIP recommended that patients with an indication for both vaccines should generally receive the conjugate vaccine first, followed a minimum of eight weeks later by the polysaccharide vaccine, and patients who have already received polysaccharide vaccine first should wait one year before receiving conjugate vaccine. (See 'Schedule for dual vaccination' above.)
Efficacy — The largest trial to assess the efficacy of PCV13 in adults was the CAPiTA trial; this trial compared PCV13 to placebo in nearly 85,000 immunocompetent adults ≥65 years of age in the Netherlands who were enrolled between 2008 and 2010 and who had not received a pneumococcal vaccine previously and who had no prior history of pneumococcal disease . The trial demonstrated 46 percent efficacy (95% CI 22 to 63 percent) of PCV13 against vaccine-type pneumococcal pneumonia, 45 percent efficacy (95% CI 14 to 65 percent) against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy (95% CI 41 to 91 percent) against vaccine-type invasive pneumococcal disease. Efficacy persisted for the duration of the trial (mean follow-up four years). There was no decrease in all-cause community-acquired pneumonia among those who received the vaccine. The number of deaths associated with pneumococcal disease was too small to allow an analysis of the effect of the vaccine on this outcome.
However, because this trial began before PCV13 was used routinely in infants in the Netherlands, it leaves unanswered the question of whether administering PCV13 to adults will prove efficacious in countries that routinely administer this vaccine to infants . Given the dramatic reduction in invasive pneumococcal disease observed in adults following the routine use of PCV in children in the United States due to the indirect ("herd") effect (figure 1), it is possible that vaccination of adults ≥65 years of age in the United States with conjugate vaccine will not provide measurable additional benefit. (See 'Overview of benefits and limitations' above.)
An additional limitation of the CAPiTA trial is that it did not have a comparative group that received PPSV23, so it did not address the question of whether PCV13 provides better protection than PPSV23 against the 13 serotypes contained within it .
A further problem in extrapolating from the CAPiTA trial to the current United States recommendations is that the trial specifically excluded subjects who were regarded as immunocompromised . Importantly, among subjects who developed an immunocompromising condition or who were placed on an immunosuppressive therapy during the period of the study, PCV13 exhibited no protective effect (22 cases of pneumococcal disease in vaccine recipients versus 24 cases in placebo recipients).
As noted above, pneumococcal conjugate vaccines have proven to be highly effective in children. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness'.)
Adverse reactions — As with PPSV, the most common adverse reactions with PCV13 include local reactions, such as erythema, swelling, pain at the injection site, and limitation of movement of the arm in which the injection was given, as well as systemic reactions, such as fatigue, headache, chills, anorexia, myalgias, and arthralgias [5,13,37]. (See "Pneumococcal conjugate vaccine (13-valent): Drug information".)
Healthcare providers should report suspected adverse events to the Vaccine Adverse Event Reporting System (VAERS). VAERS can be contacted via the VAERS website or by telephone at 800-822-7967.
Contraindications — Severe allergic reaction (eg, anaphylaxis) to any component of PCV13 or any diphtheria toxoid–containing vaccine is a contraindication to receiving PCV13 . (See "Pneumococcal conjugate vaccine (13-valent): Drug information".)
COST-EFFECTIVENESS — A cost-effectiveness analysis suggested that vaccinating adults with the 13-valent pneumococcal conjugate vaccine (PCV13) using the existing indications (ie, vaccination at age 65 years and at younger ages if comorbidities are present) would be more cost-effective than the 23-valent pneumococcal polysaccharide vaccine (PPSV23), provided that the effectiveness of PCV13 at preventing nonbacteremic pneumococcal pneumonia is high ($28,900 versus $34,600 per quality-adjusted-life-year [QALY] gained, respectively) . A major limitation of this study is that the authors relied on a meta-analysis of Huss et al , which appeared to show that PPSV23 provides no protection against noninvasive pneumococcal infection rather than on that of Moberley et al , which showed equivalent protection against invasive and noninvasive disease. Furthermore, if the indirect ("herd") effect of PCV13 is as large as has been shown for PCV7 (and results to date in the United States, United Kingdom, and France suggest that it appears to be [71,72]), infection in adults due to strains contained in PCV13 will largely be eliminated, which will render the use of the pneumococcal conjugate vaccine in adults irrelevant and will greatly increase the cost per QALY. A more recent cost analysis from the United Kingdom  recognized the indirect effect of conjugate vaccine, concluding that use of PCV13 in groups at risk for pneumococcal was not likely to be cost effective.
INVESTIGATIONAL APPROACHES — Existing pneumococcal vaccines utilize capsular polysaccharides as antigens. Vaccines cannot include all serotypes, replacement strains appear, and pneumococci readily acquire DNA from other microorganisms by transformation, giving them the ability to switch capsular serotypes. These facts have led to attempts to develop vaccines based on highly conserved proteins (eg, pneumolysin, histidine triad protein D, surface proteins A and C), some of which are surface expressed and one of which (pneumolysin) contributes substantially to the pathogenesis of pneumococcal disease. Several such vaccines are in development [32,39,74]. Data suggest that these proteins by themselves, or as proteins to which capsular polysaccharides are conjugated, might be useful in developing new pneumococcal vaccines .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Vaccines for adults (The Basics)" and "Patient education: Vaccines (The Basics)")
●Beyond the Basics topic (see "Patient education: Pneumonia prevention in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Pneumococcal infections, including pneumonia and invasive disease such as bacteremia and meningitis, remain an important source of morbidity and mortality in adults, especially among older adults (table 1) and those with certain conditions, including immunocompromising conditions and asplenia. (See 'Introduction' above.)
●Two types of pneumococcal vaccines are approved for use in the United States:
•A pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23) that includes 23 purified capsular polysaccharide antigens
•A pneumococcal protein-conjugate vaccine (PCV13; Prevnar 13) that includes capsular polysaccharide antigens covalently linked to a nontoxic protein that is nearly identical to diphtheria toxin (see 'Available vaccines' above)
●PPSV has been used in adults for decades in the United States but is not recommended for infants or toddlers <2 years of age because it is poorly immunogenic in this age group. (See 'Available vaccines' above.)
●A 7-valent pneumococcal conjugate vaccine (PCV7) was recommended by the United States Advisory Committee on Immunization Practices (ACIP) for universal use in infants and toddlers from 2000 until 2010; since 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for infants and children in its place.
Vaccination of infants and toddlers has led to a remarkable decrease in disease due to vaccine recipients (98 percent for PCV7 and >90 percent for PCV13).
Because PCV eliminates nasal carriage, young children, who traditionally have served as the source of spread of infection to adults, no longer carry pneumococcal serotypes contained within the vaccine. As a result of this indirect ("herd") effect, disease in adults due to PCV7 serotypes has decreased by >90 percent, and disease due to PCV13 serotypes is rapidly decreasing.
In 2012, the ACIP recommended PCV13 for selected high-risk adults and, in 2014, the ACIP began recommending PCV13 for all adults ≥65 years of age. (See 'Available vaccines' above.)
●The indications (table 3) and schedule (table 4) for pneumococcal vaccination depend upon age and risk factors for pneumococcal disease. We agree with the ACIP that adults of any age with the high-risk conditions listed below should receive both PCV13 and PPSV23. However, in contrast to the ACIP, we give only PPSV23 (but not PCV13) to otherwise healthy individuals aged ≥65 years:
•In accordance with the ACIP, for adults 19 to 64 years of age at intermediate risk of pneumococcal disease (ie, cigarette smokers; patients with chronic heart disease, chronic lung disease, diabetes mellitus, alcoholism, or chronic liver disease), we recommend pneumococcal vaccination (Grade 1B). Such patients should receive PPSV23 alone (algorithm 1).
•In accordance with the ACIP, for adults aged 19 or older who are at high risk of pneumococcal disease (ie, patients with functional or anatomic asplenia, an immunocompromising condition [eg, HIV infection, cancer], a cerebrospinal fluid leak, a cochlear implant, advanced kidney disease), we recommend pneumococcal vaccination with PCV13 followed at least eight weeks later by PPSV23 (Grade 1B). In patients who have already received PPSV23, at least one year should elapse before they are given PCV13.
•For all adults ≥65 years of age, we recommend pneumococcal vaccination (Grade 1B). The ACIP states that individuals ≥65 years of age should receive both PCV13 and PPSV23 (algorithm 5). In contrast, for individuals ≥65 years of age without any of the high-risk conditions described in the previous bullet, we give PPSV23 (but not PCV13). We do, however, favor the use of both PCV13 and PPSV23 in adults ≥65 years of age who have one of the conditions for which PPSV23 is indicated before age 65 (cigarette smokers; patients with chronic heart disease, chronic lung disease, diabetes mellitus, alcoholism, or chronic liver disease). We also use both PCV13 and PPSV23 in patients ≥65 years of age who are planning to travel to a country that does not have a universal immunization program mandating pneumococcal conjugate vaccine administration for all infants and toddlers. The vaccination approach for immunocompromised patients (algorithm 2) and asplenic patients (algorithm 3) as well as patients with a CSF leak, cochlear implant, or history of invasive pneumococcal disease (algorithm 4) is summarized in algorithms. It is preferable to give PCV13 first, followed by PPSV23 ≥1 year later. If PPSV23 is given first, PCV13 should be given ≥1 year later.
•PCV13 is not recommended for healthy adults <65 years of age who do not have a specific risk factor for pneumococcal infection. (See 'Indications' above.)
●The schedule for revaccination with PPSV23 depends on the patient's age and underlying diseases:
•For immunocompromised patients and individuals with functional or anatomic asplenia who are <65 years of age, the ACIP recommends one single revaccination with PPSV23 ≥5 years after the first dose. However, for asplenic individuals, some European public health agencies recommend reimmunization with PPSV23 every five years; we agree with this approach.
•The ACIP recommends a single revaccination with PPSV23 in adults ≥65 years of age if they received this vaccine before age 65; it should be administered five or more years after the previous dose. We agree with the ACIP's recommendation for revaccination with PPSV23 at or after age 65; however, following this dose (and in contrast to the ACIP), we also favor revaccinating older adults at 10-year intervals because immunologic responses wane in older adult patients. (See 'Revaccination' above.)
●Revaccination with PCV13 is not recommended. (See 'Revaccination' above.)
●PPSV23 and PCV13 are each administered intramuscularly as a 0.5 mL dose. They may be administered concurrently with other vaccines, such as the influenza vaccine, but at a separate site. However, PPSV23 and PCV13 should be administered at different times as outlined above. (See 'Administration' above and 'Schedule for dual vaccination' above.)
●The trend for vaccine strains to disappear from the population following universal immunization of infants may substantially reduce the potential benefit of PCV13 use in adults. The ACIP has stated that they will reconsider the recommendations for the use of PCV13 in adults in 2018. (See 'Indications' above and 'Overview of benefits and limitations' above and 'Efficacy' above.)
●Indirect evidence for a possible benefit of pneumococcal conjugate vaccine over PPSV23 in immunocompromised adults comes from randomized trials in HIV-infected individuals in Africa, which demonstrated a reduction in invasive pneumococcal disease among individuals who received PCV7 but no reduction in recipients of PPSV23. These trials were not, however, entirely comparable. In a large placebo-controlled trial of individuals ≥65 years of age in the Netherlands, PCV13 reduced the risk of vaccine-type pneumococcal pneumonia, vaccine-type nonbacteremic pneumococcal pneumonia, and vaccine-type invasive pneumococcal disease; this trial did not include a group that received PPSV23. (See 'Efficacy' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dr. Elaine Tuomanen and Dr. Patricia Hibberd, who contributed to earlier versions of this topic review.
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