A dynamic model of pneumococcal infection in the United States: Implications for prevention through vaccination
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)
- et al.
Effectiveness of a 2 + 1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway
Vaccine
(2008) - et al.
An easy method for detection of nasopharyngeal carriage of multiple Streptococcus pneumoniae serotypes
J Microbiol Methods
(2008) - et al.
Effectiveness of 7-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study
Lancet
(2006) - et al.
Uptake of pneumococcal conjugate vaccine among children in the 1998–2002 United States birth cohorts
Am J Prev Med
(2008) - et al.
Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine
N Engl J Med
(2003) - et al.
Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae
N Engl J Med
(2006) - et al.
Seven-valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates
Pediatr Infect Dis J
(2004) - et al.
Invasive pneumococcal disease caused by non-vaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage
JAMA
(2007) - et al.
Post-PCV7 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004
Pediatrics
(2005) - et al.
Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children
JAMA
(2007)