INTRODUCTION — Streptococcus pneumoniae (pneumococcus) is a leading cause of serious illness among children worldwide [1,2]. Before universal infant immunization with pneumococcal conjugate vaccine in the United States, S. pneumoniae caused approximately 17,000 cases of invasive disease each year among children younger than five years of age, including 700 cases of meningitis and 200 deaths [1]. It was the most frequent cause of bacteremia, bacterial pneumonia, bacterial meningitis, sinusitis, and acute otitis media.
The impact of universal infant immunization with pneumococcal conjugate vaccines on invasive serotypes, nasopharyngeal flora, and antibiotic resistance in children in the United States will be reviewed here. Pneumococcal conjugate and polysaccharide vaccines also are discussed separately. (See "Pneumococcal vaccination in children" and "Pneumococcal vaccination in adults".)
BACKGROUND — The 7-valent pneumococcal conjugate vaccine (PCV7) was added to the schedule of recommended vaccines for children younger than two years of age in the United States in 2000 [1]. PCV7 contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F conjugated to a mutant of diphtheria toxoid (table 1). The routine use of PCV7 resulted in a decreased incidence of invasive pneumococcal disease in children. (See "Pneumococcal vaccination in children", section on 'Invasive disease'.)
However, increasing data suggested that universal infant immunization with PCV7 changed the serotype patterns of invasive disease, nasopharyngeal (NP) colonization, and antibiotic resistance patterns. In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13 (table 1)) replaced PCV7 in the routine childhood immunization schedule [2].
In 2022, a 15-valent pneumococcal conjugate vaccine (PCV15 (table 1)) was licensed for use in children in the United States. In addition to the serotypes in PCV13, PCV15 contains serotypes 22F and 33F, which accounted for 15 percent of invasive pneumococcal disease (IPD) cases in children <5 years of age and 23 percent of IPD cases in children age 5 to 18 years in multisite surveillance in the United States during 2018 to 2019 [3,4]. PCV15 can be used interchangeably with PCV13 in children <18 years.
A 20-valent pneumococcal conjugate vaccine (PCV20) is in Phase III clinical trials in children [5,6].
EFFICACY — Surveillance after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) to the standard childhood immunization schedule demonstrated that pneumococcal conjugate vaccines (PCVs) are effective in preventing invasive pneumococcal disease (IPD) and providing herd immunity [7,8], as demonstrated by declining trends in invasive pneumococcal disease in children and adults [9]. The greatest decline has been noted in pneumococcal bacteremia without a focus.
The efficacy of universal infant immunization with PCV in the United States on the incidence of IPD in children and adults is discussed separately. (See "Pneumococcal vaccination in children", section on 'Efficacy and effectiveness'.)
INVASIVE DISEASE
Replacement serotypes — After the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7), there was an increase in the proportion of cases of invasive pneumococcal disease (IPD) caused by nonvaccine serotypes (ie, replacement serotypes), including serotypes 19A, 6C, and 22F, and serogroups 15 and 33 [7,10-20]. However, the increase in IPD caused by nonvaccine serotypes was small compared with the overall decline in IPD (figure 1) [10]. (See "Pneumococcal vaccination in children" and "Pneumococcal vaccination in children", section on 'Efficacy and effectiveness'.)
After the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the United States, in population-based surveillance, there was little change in the incidence of IPD caused by nonvaccine serotypes among children younger than five years in the United States (figure 2) [21,22]. However, an increase in IPD caused by nonvaccine serotypes among adults age 50 to 64 suggested serotype replacement. In surveillance from eight children's hospitals, the most common non-PCV13 serotypes isolated from children hospitalized with IPD from 2014 to 2017 were 35B, 23B, 33F, and 22F [23]. In Centers for Disease Control and Prevention (CDC) surveillance of IPD in children <5 years of age, non-PCV13 serotypes 23B, 22F, 33F, 15C, 15A, and 35 B were the most common non-PCV13 serotypes causing IPD in 2015 and 2016 [22]. Similarly, since introduction of pneumococcal conjugate vaccines in Europe, there has been an increase in IPD caused by nonvaccine serotypes (particularly 8, 12F, and 24F), although the magnitude of the increase, serotypes, and specific clinical syndromes vary from country to country [24-29].
Serotypes 8, 12F, 22F, and 33F are included in the 15-valent pneumococcal conjugate vaccine (PCV15), which has been licensed in the United States for use in individuals ≥6 weeks of age and the 20-valent pneumococcal conjugate vaccine (PCV20), which has been licensed in the United States for use in individuals ≥18 years of age (table 1) [3,30].
Surveillance reports highlight the ability of pneumococcus to adapt to vaccine selective pressure and the need to remain vigilant for invasive disease caused by nonvaccine serotypes. Factors other than the use of pneumococcal conjugate vaccines (eg, patterns of antibiotic use) may contribute to IPD epidemiology [24,31-33].
PCV13 serotypes
Serotype 19A — After introduction of PCV7, serotype 19A was frequently isolated from children with IPD, multidrug-resistant acute otitis media, coalescent mastoiditis, and chronic sinusitis [7,20,34-40]. It is included in PCV13 (table 1), which replaced PCV7 in 2010. In surveillance from eight children's hospitals after licensure of PCV13, IPD due to serotype 19A declined substantially, but remains one of the most frequently isolated serotypes [23,41]. In CDC surveillance of IPD in children <5 years of age, serotype 19A remains a common cause of IPD due to PCV13 serotypes [22].
Other PCV13 serotypes — In CDC surveillance, serotypes 19F, 3, and 5 (in addition to 19A) were the most common PCV13 serotypes causing IPD in children <5 years of age from 2014 to 2016 [22]. In surveillance from eight children's hospitals in the United States, serotypes 3 and 19F (in addition to 19A) were the most common serotypes causing IPD in children during 2014 to 2017, accounting for approximately 25 percent of cases [23].
Clinical disease — Introduction of PCV may be associated with changes in the clinical features of IPD. In single-state surveillance after licensure of PCV13, IPD caused by nonvaccine serotypes was more frequent among children with underlying conditions (eg, chronic lung disease, malignancy, immunosuppressive therapy, asthma, sickle cell disease, asplenia) than children without underlying conditions (27 versus 17 percent) [42].
NASOPHARYNGEAL COLONIZATION — Most studies evaluating the effects of universal immunization with the pneumococcal conjugate vaccine (PCV) on nasopharyngeal (NP) carriage have shown that vaccination does not change the overall rate of pneumococcal carriage [18,43-46]. However, it reduces the acquisition of vaccine serotypes and increases the acquisition of nonvaccine serotypes, as described below.
PCV serotypes — Conjugate vaccines reduce NP carriage of the serotypes included in the vaccine (table 1) [43-52]. Serotype-dependent prevention of colonization is mediated by capsule-specific memory B cells and immunoglobulin G that cause antibody-mediated agglutination of bacteria [53].
In a cross-sectional study, NP cultures were obtained from children <7 years of age at well-child and acute-care visits in primary care practices in Massachusetts communities between 2001 and 2014 [52]. Pneumococcal colonization rates ranged from 23 to 32 percent and declined in the first few years after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) and the 13-valent pneumococcal conjugate vaccine (PCV13). Colonization with vaccine serotypes also declined after introduction of PCV7 and PCV13.
Non-PCV serotypes — Pneumococcal vaccination in children is associated with increases in the nasal carriage of nonvaccine serotypes [43,44,47-49,52,54].
In a cross-sectional study, NP cultures were obtained from children <7 years of age at well-child and acute-care visits in primary care practices in Massachusetts communities between 2001 and 2014 [52]. NP carriage of non-PCV7 serotypes increased from 15 to 29 percent in children <7 years of age between 2001 and 2007, with significant increases in serotypes 19A, 35B, 23A, and 7F [55]. The most common non-PCV7 serotypes were 11, 15, and 29. After PCV13 replaced PCV7, the most common non-PCV13 serotypes colonizing the NP included 15B/C, 35B, 23B, 11A, and 23A [52].
The clinical implications of these changes in NP colonization remain to be determined. The effect of colonization with nonvaccine serotypes, some of which are penicillin-resistant, will depend upon the ability of the new serotypes to cause local (eg, otitis media) or invasive disease [56,57]. Genomic analysis of nasopharyngeal isolates from children with sickle cell disease who were vaccinated with PCV7 clearly indicated a shift away from vaccine serotypes while maintaining virulence genes [58]. This suggests that nonvaccine serotypes are circulating in the sickle cell population and they appear to remain virulent [58].
Staphylococcus aureus — Nasal carriage of Staphylococcus aureus in children appears to be inversely related to NP carriage of pneumococcal vaccine serotypes [59,60]. A potential concern with S. aureus carriage is the increasing frequency of community-associated methicillin-resistant S. aureus infections. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'CA-MRSA infection'.)
Community (herd) effects — Immunization of children with conjugate vaccines also may reduce NP colonization among their unvaccinated younger siblings, other unvaccinated household contacts, and community members [45,61-66].
ANTIBIOTIC RESISTANCE — The resistance of pneumococci to a variety of antimicrobial agents is a worldwide health problem. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" and "Resistance of Streptococcus pneumoniae to the macrolides, azalides, lincosamides, and ketolides".)
Invasive isolates — Data from Active Bacterial Core surveillance areas in the United States indicate declines in overall antibiotic-nonsusceptible invasive pneumococcal disease (IPD) after the introduction to the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 (figure 3) and after PCV7 was replaced with the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010, particularly in vaccine serotypes [67-70].
However, from 2009 to 2018, antibiotic nonsusceptibility increased in non-PCV13 serotypes. During 2014 to 2018, the most common nonsusceptible non-PCV13 serotypes in all age groups were 35B, 33F, 22F, and 15A [70]. Serotypes 22F and 33F accounted for approximately 20 percent of nonsusceptible IPD; they are included in the 15-valent pneumococcal conjugate vaccine (PCV15). The additional serotypes in the 20-valent vaccine (table 1) accounted for approximately 35 percent of nonsusceptible IPD. Surveillance from eight children's hospitals in the United States also found an increase in the proportion of invasive non-PCV13 isolates nonsusceptible to penicillin and ceftriaxone after the introduction of PCV13 [23,41]. During 2014 to 2017, approximately 10 percent of IPD isolates from eight children's hospitals in the United States had ceftriaxone minimum inhibitory concentrations nonsusceptible for the treatment of central nervous system infections [23].
Two factors are thought to be responsible for the reduction in antibiotic-resistant strains in the pneumococcal conjugate vaccine (PCV) era [61,71]:
●Immunization with PCV decreases acquisition of vaccine serotypes that are antibiotic resistant
●Recipients of PCV receive less antibiotic therapy than nonvaccinated children, further reducing the selective pressure to acquire resistant strains
Ongoing surveillance is necessary. Although the rate of IPD and antibiotic resistance among IPD isolates continues to decline, increasing proportions of antibiotic nonsusceptible IPD isolates are serotypes that are not included in PCV13 or PCV15 (eg, 35B, 15B, 23A, 23B) [72-75].
Nasopharyngeal isolates — Studies evaluating the effect of universal vaccination of infants with PCV on the antibiotic resistance of strains carried in the nasopharynx have inconsistent findings. Some demonstrate a decline in penicillin nonsusceptible isolates [46,52,76,77] and others no change [78], or an increase in isolates nonsusceptible to penicillin and other antibiotics [79,80].
The inconsistency of findings suggests that factors other than immunization with PCV may play a role in the antibiotic susceptibility patterns of pneumococcal isolates from the nasopharynx. The pattern of antimicrobial use by the community and the individual may be one such factor [81].
These observations highlight the need to continue to monitor the antibiotic resistance patterns of strains of pneumococcus carried in the nasopharynx and the use of antibiotics with potential to promote multidrug resistance.
VACCINE LIMITATIONS — The use of pneumococcal conjugate vaccines in children has reduced the incidence of invasive pneumococcal disease. However, the issue of eliminating noninvasive disease remains critical. Even if the vaccines as currently formulated substantially decrease the incidence of upper respiratory infection, the effect is not likely to be permanent.
The hallmark of pneumococci is their ease of natural DNA transformation as evidenced by their genetic diversity and the rapidity of spread of antibiotic resistance. A strain can enter a daycare center as one serotype and acquire another serotype capsule within just a few days [82].
The molecular flexibility in the capsular locus is based upon its modular gene structure [83]. There are no known limits to capsular exchangeability. Under antibody selective pressure, pneumococci can be expected to quickly evolve to circumvent vaccines that contain a limited number of serotypes. As described above, there are data to suggest this process has begun. The only long-term solution to this problem is the development of a vaccine containing one or several protective protein antigens from pneumococcus rather than serogroup-specific polysaccharide antigens [84].
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 email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Beyond the Basics topics (see "Patient education: Why does my child need vaccines? (Beyond the Basics)" and "Patient education: Vaccines for infants and children age 0 to 6 years (Beyond the Basics)")
SUMMARY
●Efficacy of pneumococcal conjugate vaccines – The incidence of invasive pneumococcal disease (IPD) in the United States has declined dramatically since the pneumococcal conjugate vaccine was added to the routine childhood immunization schedule. The greatest decline has been noted in pneumococcal bacteremia without a focus. (See 'Efficacy' above.)
●Effects on invasive disease
•The large decline in cases of IPD caused by serotypes in the 7-valent pneumococcal conjugate vaccine (PCV7) (table 1) was accompanied by a small increase in the number of cases of IPD caused by nonvaccine serotypes (eg, replacement serotypes) (figure 1). Most of the replacement serotypes are included in the 13-valent pneumococcal conjugate vaccine (PCV13) or the 15-valent pneumococcal conjugate vaccine (PCV15), which have replaced PCV7 in the United States. (See 'Invasive disease' above.)
•Among children receiving PCV7, serotype 19A was an important cause of IPD by replacement serotypes. Serotype 19A is included in PCV13, which was introduced in 2010, and PCV15, which was introduced in 2022. However, it remains an important cause of IPD. (See 'Serotype 19A' above.)
●Effects on nasopharyngeal colonization – Universal infant immunization does not appear to have affected the overall rate of carriage of pneumococcus in the nasopharynx. However, universal immunization has reduced carriage of vaccine serotypes and increased carriage of nonvaccine serotypes and Staphylococcus aureus. The clinical implications of these changes in nasopharyngeal colonization remain to be determined. (See 'Nasopharyngeal colonization' above.)
●Effects on antibiotic resistance
•Although universal infant immunization with pneumococcal conjugate vaccines (PCV7 and PCV13) has been associated with a decrease in the rate of penicillin-nonsusceptible and multiple antibiotic-nonsusceptible IPD (figure 3), antibiotic susceptibility has increased among nonvaccine serotypes. (See 'Invasive isolates' above.)
•Data regarding the effects of universal infant immunization on the antibiotic resistance patterns of isolates from the nasopharynx are inconsistent. (See 'Nasopharyngeal isolates' above.)
