Elsevier

Vaccine

Volume 28, Issue 21, 7 May 2010, Pages 3650-3660
Vaccine

A dynamic model of pneumococcal infection in the United States: Implications for prevention through vaccination

https://doi.org/10.1016/j.vaccine.2010.03.030Get rights and content

Abstract

Universal infant vaccination with the 7-valent pneumococcal conjugate vaccine (PCV7) has nearly eliminated PCV7-serotype invasive pneumococcal disease (IPD) in young U.S. children, but has been accompanied by increases in the incidence of serotype 19A IPD. Because antibiotic-non-susceptible 19A has increased more than antibiotic-susceptible 19A, antibiotic selection pressure could be contributing to this trend. We developed a dynamic compartmental transmission model of pneumococcus to better understand the causes of this rise and to estimate the impact of vaccines or changes in antibiotic use on future IPD incidence in the U.S. in <2 year-olds. The model predicted that with current practices, serotype 19A IPD incidence will plateau at about the 2007 level over the next few years. The model suggests that antibiotic usage played a major role in the rise in antibiotic-non-susceptible 19A IPD, with a lesser contribution from PCV7 vaccination. However, hypothetical large decreases in antibiotic use starting in 2008 are predicted to yield only gradual decreases in antibiotic-non-susceptible 19A IPD. On the other hand, vaccines with modest (20%) effectiveness against 19A (or 6A or PCV7-serotypes) carriage are predicted to substantially (by 80%) decrease the incidence of IPD caused by those serotypes within 10 years of implementation. Our findings highlight that vaccine effects on colonization are key to their overall benefits. In addition, serotype changes following vaccine introduction may have multifactorial origins, with antibiotic use an important factor for resistant strains such as 19A.

Introduction

Streptococcus pneumoniae is a common childhood pathogen causing illnesses ranging from mild ear infections to more severe invasive pneumococcal disease (IPD) syndromes such as meningitis and bacteremia. The introduction in the U.S. in 2000 of the 7-valent pneumococcal conjugate vaccine (PCV7; Prevenar™/Prevnar™), which targets the seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) most commonly associated with IPD in U.S. children, has led to decreases in overall IPD in children and adults, and near elimination of PCV7-serotype IPD in <2 year-olds [1], [2]. The decrease in IPD among unvaccinated older children and adults suggests that reduced transmission from vaccinated children has indirectly benefited unvaccinated populations [2].

Since vaccine introduction, several U.S. studies have reported increases in nasopharyngeal colonization [3], [4], [5], otitis media [6], and IPD [4], [7], [8], [9] caused by serotype 19A. However, even in regions where there have been significant increases in 19A, the overall incidence of IPD remains low [8], [10] relative to pre-vaccine levels, with the exception of a remote region of Alaska [4]. As increases in 19A IPD have not been universally observed in all U.S. surveillance sites [11], [12], it is unclear whether they are causally related to PCV7 use. The incidence of serotype 19A was increasing in some countries before PCV7 introduction [13], [14], it has not significantly increased in other countries that have introduced PCV7 (Norway [15], Denmark [16] and Germany [17]), and it has increased in some countries without substantial PCV7 use [18], [19]. The observed increases in 19A and other non-PCV7-serotypes could thus conceivably be due to several factors including (but not limited to) vaccine introduction, antibiotic pressure favoring the spread of resistant clones, secular trends [17] and capsular switching [7].

To assess the relative contributions of some of these factors, we developed a dynamic compartmental model of pneumococcal transmission. We hypothesized that the key determinants of a conjugate vaccine impact on IPD are its effects against nasopharyngeal colonization and against IPD once colonized, and that these effects need to be analysed separately in such a model. Similarly, we also treated antibiotic-susceptible and non-susceptible isolates separately as antibiotic pressure/treatment influences nasopharyngeal carriage, and we accounted for changes in antibiotic use over time and the distinct effects of different classes of antibiotics on carriage. Our model focused on the population aged <2 years in the U.S., because this is the population with the highest rates of IPD before PCV7 introduction and the highest prevalence of nasopharyngeal carriage, and for which the most data are available.

The model allowed us to take into account the complexities of colonization and transmission while evaluating the potential impact of antibiotic use and of vaccines with varying effects on serotype-specific IPD.

Section snippets

Methods

Our dynamic compartmental model focused on the <2 year-old population and took into account the natural history of S. pneumoniae (colonization, natural clearance and competition between serotypes in the nasopharynx), as well as the effects of antibiotic treatment and vaccination on colonization. In the model, a child may be either not colonized with pneumococcus (NC), colonized with a single serotype (C), or co-colonized with two different serotypes (CC), and may be under the influence of

Observed trend in IPD for 19A serotype and antibiotic use

To better understand whether we needed to explicitly take antibiotic susceptibility status into account in the model, we plotted the annual incidence of IPD cases in <2 year-olds caused by 19A susceptible (19A-S) to amoxicillin and erythromycin separately from IPD cases caused by 19A non-susceptible (19A-NS) to amoxicillin or erythromycin (Fig. 2a). Fig. 2a indicates that the kinetics and extent of changes in 19A IPD incidence over the last 10-year period appeared to be quite different for

Discussion

We found that using assumptions based primarily on published data it was possible to develop a dynamic compartmental model that closely reproduced the serotype-specific changes in IPD seen in U.S. children <2 years-old since 2000. Several conclusions can be drawn from the projections given by this model.

Firstly, the model was unable to reproduce the observed increase in 19A-NS IPD unless we assumed that Ab-NS serotype 19A colonization was already increasing at the time of PCV7 introduction.

Acknowledgements

The authors thank Anna Dow (Freelance) for scientific writing support and Christine Vanderlinden (GlaxoSmithKline Biologicals) for editorial assistance and manuscript coordination. They also thank Jonathan Finkelstein (Department of Population Medicine; Harvard Pilgrim Health Care Institute and Harvard Medical School) for sharing Massachusetts carriage data, and Cosmina Hogea (GlaxoSmithKline Biologicals) for very useful discussions about the model. The authors also acknowledge the clinicians,

References (62)

  • M.R. Moore et al.

    Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005

    J Infect Dis

    (2008)
  • S.I. Pelton et al.

    Emergence of 19A as virulent and multidrug-resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine

    Pediatr Infect Dis J

    (2007)
  • A.F. Messina et al.

    Impact of the pneumococcal conjugate vaccine on serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae isolates in Dallas, TX, children from 1999 through 2005

    Pediatr Infect Dis J

    (2007)
  • L.A. Hicks et al.

    Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998–2004

    J Infect Dis

    (2007)
  • S. Black et al.

    Surveillance for invasive pneumococcal disease during 2000-2005 in a population of children who received 7-valent pneumococcal conjugate vaccine

    Pediatr Infect Dis J

    (2007)
  • R. Lacapa et al.

    Changing epidemiology of invasive pneumococcal disease among White Mountain Apache persons in the era of the pneumococcal conjugate vaccine

    Clin Infect Dis

    (2008)
  • E. Bingen et al.

    Pneumococcal meningitis in the era of pneumococcal conjugate vaccine implementation

    Eur J Clin Microbiol Infect Dis

    (2008)
  • G. Hanquet

    Dynamic changes of three non-vaccine pneumococcal serotypes in Spain, France, Belgium, England and Wales

  • Harboe ZB, Valentiner-Branth P, Benfield TL, Christensen JJ, Andersen PH, Howitz M, et al. Early effectiveness of...
  • M. van der Linden et al.

    Surveillance of IPD in children in Germany 2004–2008; first results of the German national immunization program for PCV7

  • E. Hwa Choi et al.

    Streptococcus pneumoniae serotype 19A in children, South Korea

    Emerg Infect Dis

    (2008)
  • R. Dagan et al.

    Introduction and proliferation of multidrug-resistant Streptococcus pneumoniae serotype 19A clones that cause acute otitis media in an unvaccinated population

    J Infect Dis

    (2009)
  • K.L. O’Brien et al.

    Report from a WHO working group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae

    Pediatr Infect Dis J

    (2003)
  • R. Dagan et al.

    Will reduction of antibiotic use reduce antibiotic resistance?: The pneumococcus paradigm

    Pediatr Infect Dis J

    (2006)
  • F. Ghaffar et al.

    Effects of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children with acute otitis media

    Clin Infect Dis

    (2000)
  • F. Ghaffar et al.

    Effects of large dosages of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, non-pneumococcal alpha-hemolytic streptococci, and Staphylococcus aureus in children with acute otitis media

    Clin Infect Dis

    (2002)
  • K.L. Sleeman et al.

    Capsular serotype-specific attack rates and duration of carriage of Streptococcus pneumoniae in a population of children

    J Infect Dis

    (2006)
  • A.B. Brueggemann et al.

    Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential

    J Infect Dis

    (2003)
  • K. Trzcinski et al.

    Incremental increase in fitness cost with increased beta -lactam resistance in pneumococci evaluated by competition in an infant rat nasal colonization model

    J Infect Dis

    (2006)
  • N. Wolter et al.

    Heterogeneous macrolide resistance and gene conversion in the pneumococcus

    Antimicrob Agents Chemother

    (2006)
  • R. Dagan et al.

    Seasonality of antibiotic-resistant Streptococcus pneumoniae that causes acute otitis media: a clue for an antibiotic-restriction policy?

    J Infect Dis

    (2008)
  • Cited by (0)

    View full text