Impact of Universal Infant Immunization With Pneumococcal Conjugate Vaccines in The United States - UpToDate

5/11/2020 Impact of universal infant immunization with pneumococcal conjugate vaccines in the United States - UpToDate
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Impact of universal infant immunization with pneumococcal

conjugate vaccines in the United States
Author: Elaine I Tuomanen, MD
Section Editor: Sheldon L Kaplan, MD
Deputy Editor: Mary M Torchia, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2020. | This topic last updated: Dec 10, 2019.
INTRODUCTION
Streptococcus pneumoniae (pneumococcus) is a leading cause of serious illness among children worldwide
[1]. 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 [1].
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, there were increasing data to suggest 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) replaced PCV7 in the routine childhood
immunization schedule [2].
The impact of universal infant immunization with PCV7 and PCV13 on invasive serotypes, NP flora, and
antibiotic resistance in children in the United States will be reviewed here. The impact in adults is discussed
separately. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section
on 'Impact of childhood vaccination'.)
Pneumococcal conjugate and polysaccharide vaccines also are discussed separately. (See "Pneumococcal
vaccination in children" and "Pneumococcal vaccination in adults".)
EFFICACY
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Surveillance after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) to the standard
childhood immunization schedule has shown that pneumococcal conjugate vaccines (PCVs) are effective in
preventing invasive pneumococcal disease (IPD) and providing herd immunity (figure 1) [3]. In 2003, it was
estimated that 29,599 cases of vaccine serotype IPD were prevented through routine immunization.
Approximately two-thirds of these cases were prevented through herd immunity [4]. 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 in detail separately. (See "Invasive pneumococcal (Streptococcus
pneumoniae) infections and bacteremia", section on 'Impact of childhood vaccination' and "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 [3-14]. However, the increase in IPD caused by nonvaccine serotypes was small compared with the
overall decline in IPD (figure 1) [4]. (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) [15,16]. However, an
increase in IPD caused by nonvaccine serotypes among adults ages 50 to 64 is suggestive of 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 [17]. 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. Similarly, since introduction of pneumococcal conjugate vaccines in Europe, there has been an
increase in IPD caused by nonvaccine serotypes (particularly 12F and 24F), although the magnitude of the
increase, serotypes, and specific clinical syndromes vary from country to country [18].
These 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 [18-
21].
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 [3,14,22-28]. 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 [17,29]. In CDC surveillance of IPD in children <5 years of age, serotype 19A remains a
common cause of IPD due to PCV13 serotypes [16].
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 [16]. 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 [17].
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) [30].
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 [12,31-34]. 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)
[31-40]. Serotype-dependent prevention of colonization is mediated by capsule-specific memory B cells and
immunoglobulin G that cause antibody-mediated agglutination of bacteria [41].
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 [40].
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 — In contrast to the inhibitory effect on vaccine serotypes, pneumococcal vaccination
in children is associated with increases in the nasal carriage of nonvaccine serotypes [31,32,35-37,40].
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 [40]. 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 [42]. 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 [40].
Receiving PCV as recommended appears to be associated with higher rates colonization with nonvaccine
serotypes [40,43].
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 [44,45]. 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 [46]. This suggests that
nonvaccine serotypes are circulating in the sickle cell population and they appear to remain virulent [46].
Staphylococcus aureus — Nasal carriage of Staphylococcus aureus in children appears to be inversely

related to NP carriage of pneumococcal vaccine serotypes [47,48]. 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'.)
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
[33,49-54].
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 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 [55-57].
Surveillance from eight children's hospitals in the United States also found a decline in the proportion of
isolates nonsusceptible to penicillin and ceftriaxone after the introduction of PCV13 [29,58]Susceptibility
results for erythromycin, clindamycin, and trimethoprim-sulfamethoxazole were unchanged [29]. However,
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 [58].
Two factors are thought to be responsible for the reduction in antibiotic-resistant strains in the pneumococcal
conjugate vaccine (PCV) era [49,59]:
● 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 (eg, 35B, 15B, 23A, 23B) [60-63].
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 [34,40,64,65] and others no change [66]. In a cross-sectional
study in which NP cultures were obtained from children <7 years of age at well-child and acute-care visits in
several Massachusetts communities, nonsusceptibility of NP isolates to penicillin declined between 2001 and
2014, but nonsusceptibility to macrolides and cephalosporins increased [40].
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 [67].
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. As has been demonstrated, a strain can enter a
daycare center as one serotype and acquire another serotype capsule within just a few days [68].
The molecular flexibility in the capsular locus is based upon its modular gene structure [69]. 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 [58].
INFORMATION FOR PATIENTS
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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
● 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
(figure 1). The greatest decline has been noted in pneumococcal bacteremia without a focus. (See
'Efficacy' above.)
● 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), which has replaced PCV7 in the
United States. (See 'Invasive disease' above.)
● Widespread use of PCV7 was associated with an increase in the proportion of cases of IPD associated
with pneumonia and/or empyema. (See "Epidemiology, clinical presentation, and evaluation of
parapneumonic effusion and empyema in children" and "Pneumococcal pneumonia in children", section
on 'Complications'.)
● 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. However, it remains an
important cause of IPD. (See 'Serotype 19A' above.)
● 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.)
● Universal infant immunization has been associated with a decrease in the rate of penicillin-
nonsusceptible and multiple antibiotic-nonsusceptible IPD (figure 3). (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.)
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Implementation in Young Children. Clin Infect Dis 2019; 69:648.
66. Gounder PP, Brewster M, Bruce MG, et al. Impact of the Pneumococcal Conjugate Vaccine and
Antibiotic Use on Nasopharyngeal Colonization by Antibiotic Nonsusceptible Streptococcus
pneumoniae, Alaska, 2000[FIGURE DASH]2010. Pediatr Infect Dis J 2015; 34:1223.
67. Greenberg D, Givon-Lavi N, Sharf AZ, et al. The association between antibiotic use in the community
and nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae in Bedouin children.
Pediatr Infect Dis J 2008; 27:776.
68. Nesin M, Ramirez M, Tomasz A. Capsular transformation of a multidrug-resistant Streptococcus

pneumoniae in vivo. J Infect Dis 1998; 177:707.
69. Caimano MJ, Hardy GG, Yother J. Capsule genetics in Streptococcus pneumoniae and a possible role
for transposition in the generation of the type 3 locus. Microb Drug Resist 1998; 4:11.
Topic 6019 Version 24.0
GRAPHICS
Comparison of serotypes in pneumococcal vaccines
Conjugate vaccines Polysaccharide vaccine
PCV7 PCV10* PCV13 PPSV23

PCV15 ¶
(Prevnar 7) (Synflorix) (Prevnar 13) (Pneumovax 23)
4 4 4 4 4 2
6B 6B 6B 6B 6B 8
9V 9V 9V 9V 9V 9N
14 14 14 14 14 10A
18C 18C 18C 18C 18C 11A
19F 19F 19F 19F 19F 12F
23F 23F 23F 23F 23F 15B
– – – – – 17F
– 1 1 1 1 20
– 5 5 5 5 22F
– – 3 3 3 33F
– 7F 7F 7F 7F –
– – 19A 19A 19A –
– – 6A 6A – –
– – – 22F – –
– – – 33F – –
PCV7: 7-valent pneumococcal conjugate vaccine; PCV10: 10-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal
conjugate vaccine; PCV15: 15-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine.
* Not available in the United States.
¶ In development.
Graphic 77274 Version 6.0
Changes in invasive pneumococcal disease incidence in

the era of the conjugate vaccine
Changes in invasive pneumococcal disease (IPD) incidence by serotype group

among children aged <5 years (A) and adults aged ≥65 years (B), 1998 to
2007.
* 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United

States for routine use among young children and infants in the second half of 2000.
From: Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive

pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010; 201:32. By
permission of the Infectious Diseases Society of America. Copyright © 2013 Oxford
University Press.
Rates of invasive pneumococcal disease among children <5 years old, United States, 2007-
2016
The rate of IPD in children <5 years of age declined after introduction of PCV13 in 2010, primarily due to declines in IPD caused by
PCV13 serotypes and serotype 6C (due to cross-protection).
PCV13: 13-valent pneumococcal conjugate vaccine; IPD: invasive pneumococcal disease; NVT: nonvaccine serotypes.
Reproduced from: Matanock A. Invasive pneumococcal disease in the U.S. – 2008-2016. ACIP meeting slides, October 2017. Available at:
https://stacks.cdc.gov/view/cdc/57593 (Accessed on September 26, 2018).
Rates of antibiotic nonsusceptible pneumococcal disease among

children
NS: nonsusceptible; MIC: minimum inhibitory concentration.

* The old/oral meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a MIC
≥0.12 mcg/mL.
¶ Not susceptible to 3 or more of the antibiotic classes tested.
Δ The new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4
mcg/mL for nonmeningitis disease and ≥0.12 mcg/mL for meningitis.
Data from: Hampton LM, Farley MM, Schaffner W, et al. Prevention of antibiotic-nonsusceptible
Streptococcus pneumoniae with conjugate vaccines. J Infect Dis 2012; 205:401.
Contributor Disclosures
Elaine I Tuomanen, MD Consultant/Advisory Boards: Matrivax [Pneumococcal vaccine]. Patent Holder: St Jude
Children’s Research Hospital [Pneumococcal vaccine]. Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support:
Pfizer [Streptococcus pneumoniae]; Merck [Staphylococcus aureus]; MeMed Diagnostics [Bacterial and viral infections].
Consultant/Advisory Board: Pfizer [Staphylococcus aureus]. Other Financial Interest: Pfizer [PCV13; linezolid]; Medscape
[Bacterial meningitis]; Elsevier [Pediatric infectious diseases]. Mary M Torchia, MD Grant/Research/Clinical Trial
Support: Pfizer [Group B Streptococcus].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

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Impact of universal infant immunization with pneumococcal

Staphylococcus aureus — Nasal carriage of Staphylococcus aureus in children appears to be inversely

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tanock.pdf (Accessed on September 26, 2018).

56. Tomczyk S, Lynfield R, Schaffner W, et al. Prevention of Antibiotic-Nonsusceptible Invasive

65. Danino D, Givon-Lavi N, Ben-Shimol S, et al. Understanding the Evolution of Antibiotic-nonsusceptible

68. Nesin M, Ramirez M, Tomasz A. Capsular transformation of a multidrug-resistant Streptococcus

Topic 6019 Version 24.0

Comparison of serotypes in pneumococcal vaccines

Conjugate vaccines Polysaccharide vaccine

PCV7 PCV10* PCV13 PPSV23

18C 18C 18C 18C 18C 11A

19F 19F 19F 19F 19F 12F

23F 23F 23F 23F 23F 15B

– – 19A 19A 19A –

Graphic 77274 Version 6.0

Changes in invasive pneumococcal disease incidence in

Changes in invasive pneumococcal disease (IPD) incidence by serotype group

* 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United

From: Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive

Graphic 64834 Version 7.0

Graphic 96718 Version 5.0

Rates of antibiotic nonsusceptible pneumococcal disease among

NS: nonsusceptible; MIC: minimum inhibitory concentration.

Graphic 54045 Version 3.0

Conflict of interest policy

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