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Invasive Pneumococcal Disease in England and Wales: Vaccination Implications

  1. Karen Sleeman1,
  2. Kyle Knox1,2,
  3. Robert George3,
  4. Elizabeth Miller3,
  5. Pauline Waight3,
  6. David Griffiths1,
  7. A. Efstratiou3,
  8. K. Broughton3,
  9. Richard T. Mayon-White1,3,
  10. E. R. Moxon1 and
  11. D. W. Crook1 on Behalf of the Public Health Laboratory Service and the Oxford Pneumococcal Surveillance Groupa
  1. 1Oxford Vaccine Group, John Radcliffe Hospital, Oxford
  2. 2Wellcome Trust Centre for Epidemiology of Infectious Diseases, Oxford University, London, United Kingdom
  3. 3Public Health Laboratory Service, Colindale, London, United Kingdom
  1. Reprints or correspondence: Dr. Derrick Crook, Dept. of Microbiology, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom (dcrook{at}molbiol.ox.ac.uk).

  1. Presented in part: “Epidemiology of Invasive Pneumococcal Disease in England and Wales: A Population-Based Surveillance,” International Symposium on Pneumococci and Pneumococcal Diseases, Sun City, South Africa, March 2000 (poster P70).

 
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Abstract

Knowledge of the epidemiology of invasive pneumococcal disease (IPD) will aid in planning the use of pneumococcal vaccines. A United Kingdom (UK)—based surveillance in England and Wales (1995–1997) of 11,528 individuals with IPD and a local enhanced surveillance in the Oxford (UK) area (1995–1999) have been analyzed. IPD has a high attack rate in children, with 37.1–48.1 cases per 100,000 infants <1 year old per year, and in older persons, with 21.2–36.2 cases per 100,000 persons >65 years old per year, for England, Wales, and Oxford. The 7-valent conjugate vaccine includes serotypes causing ⩽79% of IPD in children <5 years old, but only 66% in adults >65 years old. The data also indicate that IPD varies by serotype, age, and country, emphasizing that the epidemiology of IPD is heterogeneous and requires continued surveillance.

Streptococcus pneumoniae is considered to be one of the most important causes of serious infections and death in children and adults in both developing and developed countries [1, 2]. Prevention of such disease and death is considered a high priority [3]. The emergence and spread of resistant pneumococcal strains have led to an emphasis on the prevention of pneumococcal disease by vaccination.

A 14-valent polysaccharide vaccine was licensed in 1977 in the United States, and by 1983 a 23-valent polysaccharide vaccine was licensed and is widely used. The efficacy of this vaccine in adults with predisposing factors to pneumococcal disease is still unclear [4, 5]. In addition, this vaccine is largely ineffective in children at maximum risk, which obviates its use in routine childhood immunization programs. The polysaccharide vaccine induces a T cell—independent antibody response that is shortlived in children younger than 2 years and does not result in immunologic memory [6]. The new polysaccharide-protein conjugate vaccines enable recruitment of T cell help, thereby enhancing immunogenicity and providing immunologic memory in infants [7–9]. Efficacy trials for these vaccines have been completed in the United States and Finland and are under way in Africa, Asia, South America, Australia, and Israel. The results from the United States and Finland show that these vaccines have low reactogenicity and are efficacious, with 97% efficacy against IPD and 73% efficacy against radiologically confirmed acute respiratory infections, but limited efficacy (6%–7%) against all episodes of clinically diagnosed acute otitis media (AOM) [10–12]. Despite limited efficacy, the overall impact that these vaccines have on AOM will be significant in countries where the incidence of AOM is high and where there is a high proportion of more severe AOM requiring ventilatory tube (grommet) replacement (20% efficacy). In addition, conjugate vaccines provide protection against carriage of vaccine serotypes and may reduce the overall transmission of the pneumococcus (herd immunity) [13–15].

Knowledge of the epidemiology of invasive pneumococcal disease (IPD) will aid in planning the use of pneumococcal vaccines. The optimal age at which these vaccines are administered in each country will depend on the age-specific incidence of pneumococcal disease, and the choice of what vaccine to use should be based on epidemiological data that describe the age-specific distribution of the pneumococcal serotypes causing disease. There have been efforts to establish a timeless “global epidemiology” of the pneumococcus, but it has became apparent that the epidemiology of the pneumococcus varies by geographic region, time, age, and disease manifestation. Therefore, countries may require different formulations of the pneumococcal conjugate vaccines as stand-alone vaccines or in combination with other antigens, depending on the local epidemiology and routine vaccination schedules.

In the UK, there have been good descriptions of IPD, focusing on particular regions, clinical manifestations, and antimicrobial resistance [16–21]. However, in light of the licensure of the pneumococcal conjugate 7-valent vaccine in the United States in February 2000, and its likely introduction in the UK, an updated and comprehensive national epidemiology is required. This paper presents an analysis of data on IPD for children and adults, prospectively collected from July 1995 through December 1999 in Oxford and from 1995 through 1997 in England and Wales.

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Subjects and Methods

Description of the population

Since 1995, all laboratories (numbering 10) in the Oxford region, serving a population of 3 million people, have collaborated in the ongoing enhanced surveillance of IPD. The enhanced surveillance has been conducted by a multicenter collaborative group composed of sentinel microbiologists in all hospitals in the Oxford region. Comparable audited methods were used on a yearly basis to ensure complete reporting, and progress was assessed by group reporting every 6 months. Data for England and Wales, which included the enhanced surveillance in the Oxford region, were collected from all other regions by voluntary reporting of invasive pneumococcal isolates to the Public Health Laboratory Service (PHLS), Communicable Diseases Surveillance Centre, supplemented by referral of isolates for serotyping to the Central Public Health Laboratory. These reports come from 200–300 PHLS, National Health Service, and private laboratories combined.

Case definitions

IPD cases are defined by the isolation of S. pneumoniae from the blood, cerebrospinal fluid (CSF), or other normally sterile sites. Only 1 isolate per disease episode has been analyzed.

Bacteriology and serotyping (resistance)

S. pneumoniae was cultured and identified, and antibiotic susceptibilities were determined, by standard techniques [22]. Serotyping was performed by the Quelling reaction, using serotype-specific antiserum (Statens Seruminstitut), as described by Lund and Henrichsen [22].

Statistical analysis

The age-specific incidence was calculated by using the mid-year population by age from 1996 for England and Wales and from 1997 for Oxford [23, 24]. To calculate the annual mean incidence in the first month of life, the number of IPD cases in this age group was divided by the number of live births in that year. For the mean annual age-specific incidence by year, the number of IPD cases for all years was divided by the total population in each age band for each year and then divided by the number of years. A Poisson regression was conducted, to explore the effects of sex on the incidence of invasive disease, and a logistic regression was conducted, to determine whether the proportion of pneumococci resistant to penicillin and erythromycin changed by age and over time. Descriptive statistics were conducted for analysis of serotype distribution. Only 56% of all isolates for England and Wales were serogrouped, whereas all available isolates in Oxford were serotyped, as a part of the enhanced surveillance. All statistical analyses were conducted on Stata Release 6.

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Results

Overall incidence

For England and Wales, 10,535 cases with positive blood, CSF, or other sterile site cultures were reported between January 1995 and December 1997. The overall mean annual incidence for all ages was 6.6 per 100,000 population for IPD and 0.79 per 100,000 population for pneumococcal meningitis. The enhanced surveillance of IPD in the Oxford region recorded a total of 1288 individuals between July 1995 and December 1999. The overall mean annual incidence for the Oxford region was 9.6 per 100,000 persons for IPD and 0.78 per 100,000 population for pneumococcal meningitis. The male-to-female ratio in the Oxford region was 1.06. Men were more at risk of IPD than were women (incidence rate ratio [IRR], 1.3; 95% confidence interval [CI], 1.1–1.5; P < .001), and boys (<5 years old) were more at risk of IPD (IRR, 1.57; 95% CI, 1.2–2.2; P < .01) and pneumococcal meningitis (IRR, 2.03; 95% CI, 1.2–3.4; P < .01) than were girls of the same age (figure 1).

Figure 1
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Figure 1

Mean annual incidence of invasive pneumococcal disease, by age and sex, in England and Wales, 1995–1997, and in the Oxford region, 1995–1999.

Age-specific attack rates of IPD in adults and children

The age-specific incidences for England, Wales, and Oxford show a high attack rate of pneumococcal disease in children: 14.5–21.2 cases per 100,000 children per year for IPD and 5.5–6.2 cases per year for pneumococcal meningitis (<5 years old), 37.1–48.1 cases per 100,000 infants per year for IPD and 13.3–14.8 per 100,000 infants per year for pneumococcal meningitis (<1 year old; figures 1 and 2). The age-specific incidence in older persons (>65 years old) was 21.2–36.2 per 100,000 persons per year for IPD and 0.85–1.2 per 100,000 persons per year for pneumococcal meningitis (figures 1 and 2). Of all the IPD cases reported among children <5 years old, 34% in Oxford and 27% in England and Wales presented with meningitis. The majority of IPD cases in this age group (71%) occurred during the first 2 years of life. Among children <2 years old, 12% of cases in England and Wales and 6% of cases in Oxford occurred in the first month of life. This represented 132 cases reported nationally between 1995 and 1997 and only 7 cases within the Oxford region (0.07 and 0.04 per 1000 live births, respectively). Most of the neonatal cases (<28 days) occurred in the first week of life (80%–85%), and 10%–12% of these were meningitis cases. Data on the risk factors for neonatal cases were not available for England and Wales. In Oxford, 3 of the neonates with IPD were born prematurely.

Figure 2
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Figure 2

Mean annual incidence of pneumococcal meningitis, by age and sex, in England and Wales, 1996–1997, and in the Oxford region, 1995–1999.

Serotype distribution of IPD

The 11 most common serogroups causing IPD for all ages in England, Wales, and the Oxford region were 14, 9, 1, 19, 6, 4, 23, 3, 8, 12, and 18 (table 1). Serotypes are presented for Oxford only, because only some of those serogrouped in England and Wales were serotyped. Combined, these serogroups cause 87% of all IPD reported in England and Wales and 73% of all IPD in the Oxford region. For children <5 years old, the 11 most common serogroups isolated in England, Wales, and the Oxford region were 14, 19, 6, 18, 1, 9, 23, 4, 3, 7, and 8 (table 1). Combined, these isolates accounted for 92% of the isolates causing IPD in England and Wales and 81% of IPD in Oxford. Seventy-one percent of neonatal isolates from England and Wales were serogrouped, and 23% of these were serotype 1. An analysis of these data showed that serotype 1 (figure 3) is significantly more likely to occur in neonates (<28 days old) than in children aged between 29 days and 9 years. The prevalence of serotype 1 in the neonatal period was not significantly different from that in the young adult population. The inverse pattern was seen for serotype 14, with neonates being significantly less likely than older children to have IPD from serotype 14.

Figure 3
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Figure 3

Serotype-specific distributions of pneumococcal isolates due to serotypes 1 and 14, by age, in England and Wales, 1995–1997.

Distribution of serotypes in the polysaccharide-protein conjugate vaccines

The percentages of isolates serogrouped/serotyped and present in the pneumococcal vaccine formulations are shown for England, Wales, and Oxford in table 2. For England, Wales, and Oxford, the proportion of isolates found in the 7-valent vaccine ranges from 51% to 79%, depending on the age group, whereas the 11-valent vaccine has uniformly high coverage for all age groups. Percentages for England and Wales are based on serogroups and will incorporate other serotypes, some of which might be considered to be cross-protective. The additional cross-protection for serotypes 6A and 19A in Oxford are presented separately, because of concern over the lack of cross-protection from 6B and 19F antigens for 6A and 19A [25]. The percentages for isolates of other serotypes that fall into the same serogroup as those in the vaccine formulations are presented in table 1, although there is no evidence for cross-protection due to these serotypes.

Table 1
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Table 1

Invasive pneumococcal disease, by serogroups, in England and Wales, 1995–1997, and in the Oxford region, 1995–1999.

Drug resistance

The prevalence in Oxford of pneumococcal drug resistance is 4.6% for penicillin and 12% for erythromycin. One percent of all isolates were resistant to both erythromycin and penicillin. Isolates that were resistant to erythromycin were more common in childhood, although this was not significant (IRR, 1.37; 95% CI, 0.79–2.36). There was no age dependency for isolates that were resistant to penicillin. Resistance to trimethropin-sulfamethoxazole was not examined in this cohort of cases. A logistic regression of resistance on time showed no significant difference in the prevalence of drug resistance for penicillin and erythromycin between 1995 and 1999 in Oxford. However, the national data demonstrate a significant increase in isolates resistant to penicillin from 1.5% in 1990 [26] to 8.9% in 1997 and in isolates resistant to erythromycin from 2.8% in 1990 [26] to 13.7% in 1997.

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Discussion

Describing the age-specific patterns of IPD and the serotype distribution of isolates provides information that ensures adequate implementation of the pneumococcal conjugate vaccines. Epidemiological data of this kind also reinforce the observation that each serotype is unique not only in its age-specific incidence, but probably also in its transmission mode. The use of a local enhanced surveillance in Oxford to complement the national passive surveillance for England and Wales strengthens the validity of these results.

The incidence of IPD disease reported here is similar to that found in the rest of Europe, although lower than the incidence reported in the United States (table 3 [27–36]). The incidence of pediatric IPD is also much lower than that in the United States, with the most striking difference occurring in infants <1 year old (37.1–48.1 cases per 100,000 infants per year in England and Wales, vs. 154 cases per 100,000 population per year in the US). This may be a spurious difference arising from different medical practices between countries, such as admission thresholds and blood culture rates. The overall incidence in the Oxford region is 1.4 times higher than the overall incidence for England and Wales. This is likely to be due to the passive nature of national reporting, which is an underestimate of the true burden of IPD in England and Wales. The true estimate nationally is likely to be equivalent to the incidence in the Oxford region. Although drug resistance is low in England and Wales compared with that in some other European countries [37], an increase in prevalence reported in the national data requires continued monitoring and surveillance of resistant isolates.

Table 2
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Table 2

Percentage of invasive disease isolates covered by each conjugate vaccine.

Table 3
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Table 3

Incidence of invasive pneumococcal disease in reported studies.

Susceptibility to IPD has a clear relationship with age. Unlike Haemophilus influenzae type b and Neisseria meningitidis, disease is not concentrated in children and young adults. The incidence of disease for the pneumococcus is high in the young, remains low through adolescence and early adulthood, and then begins to rise gradually in middle adulthood, dramatically increasing in those ⩾65 years old. Disease in adulthood often occurs in the presence of risk factors that encompass a combination of medical [38–40], genetic [41–43], and social dispositions [44–47]. Several studies support the finding of a predisposition of males to IPD in both young children and adults ⩾65 years old [27, 28, 30, 48]. It is likely that the higher risk in elderly men is due to differences in the prevalence of predisposing factors, such as smoking [44].

Despite a peak of invasive pneumococcal cases in the first month of life, the pneumococcus plays a minor role in neonatal meningitis in England and Wales. S. pneumoniae is estimated to cause 3%–5% of neonatal meningitis, whereas group B streptococcus causes 28%–30%; Escherichia coli, 18%–33.4%; and Listeria monocytogenes, 5%–7% of neonatal meningitis [49, 50]. There is a paucity of data on the relative importance of pneumococcal sepsis in this age group. Although the incidence of bacteremia is higher than that of meningitis in the first month of life, the relative contribution to disease that pneumococcal bacteremia makes is difficult to determine, not least because the incidence is heavily dependent on blood culture rates, which vary between regions in the UK [51] and also between countries. In some parts of the developing world, however, S. pneumoniae is the principal cause of infections in neonates and young infants [52]. Investigating the transmission dynamics of the pneumococcus, the genetic basis of host susceptibility to invasive disease, and the placental transfer of anticapsular pneumococcal antibodies may clarify the underlying reasons for the risk of disease in the neonatal period and may also clarify immunization strategies for protecting neonates. Maternal immunization, if shown to be effective, may prove to be the most appropriate means of preventing neonatal disease and would be justified in the developing world, where the incidence of IPD is high in neonates and young infants. In the UK, the potential benefits and cost-effectiveness of implementing a vaccine strategy to prevent neonatal cases will need careful evaluation and assessment.

These epidemiological patterns may provide clues to the route of transmission for the pneumococcus and may suggest that different serotypes use different mechanisms of transmission, depending on their ability to colonize specific niches. For example, serotype 1 may be able to colonize the genital tract, but not exclusively, and/or have a higher transmissibility associated with it. However, these results are indicative only of the relative contribution of serogroups to disease patterns, because 29% of neonatal isolates were not serogrouped in the national database.

In this study, serogroups 14, 19, 6, 18, 1, 9, 23, 4, 3, 7, and 8 were found to cause 81%–93% of IPD in children <5 years old. It is clear that serotypes 14, 19, 6A, 6B, and 23F, although varying in rank order, are the most common serotypes causing IPD in children [27, 28, 33, 36, 53–57]. These serotypes are also commonly carried and, as such, have become dominant. Serotypes 1 and 18C, though previously recorded as “developing” and “developed” country serotypes, respectively [58], are also global, with serotype 1 being responsible for a number of outbreaks in adults [59–62]. In this survey, serotype 1 was found to cause 10%–12% of all invasive disease. Although this serotype is not generally common in pediatric disease, it amounts to 23% of the neonatal (<28 days old) isolates reported and serotyped by the PHLS. This illustrates that pneumococcal serotypes do not necessarily fall into simple patterns and can vary both temporally and geographically. To make sound policy decisions, we can no longer rely on epidemiological descriptions of the pneumococcus as being characteristic of “developing” or “industrialized” countries.

The 11-valent vaccine covers the highest proportion of serotypes causing disease in all age groups. However, the additional benefits of a marginal increase in the number of serotypes must be weighed against the cost of producing vaccines with larger valency. In older adults, the 11-valent vaccine formulation increases the number of isolates covered by 15%, in comparison with the number covered when the 7-valent formulation is used, and, as such, may be considered more cost effective. The diversity of serotypes in the older age group demands consideration of a vaccine with a high valency (i.e., the 11-valent vaccine). However, its potential benefits will need to be assessed in comparison with those of the currently available 23-valent polysaccharide vaccine.

Because the conjugate vaccines affect the host's ability to acquire and carry the pneumococcus, replacement of vaccine serotypes by nonvaccine serotypes or other organisms is a concern. The effect that such replacement has on the incidence of IPD is unknown. A 34% increase in nonvaccine serotypes causing AOM has been reported after a 3-dose 7-valent conjugate vaccine was given in infancy [12] Despite this, there was still an overall reduction by 34% (21%–45%) in all middle-ear fluid culture proven to be pneumococcal AOM. The ability of pneumococci to switch capsules through genetic recombination, while maintaining their disease-causing virulence factors [63], further complicates the prevention of disease by vaccination. Therefore, national epidemiological surveillance on IPD is essential with the introduction of these new conjugate vaccines.

The pneumococcal conjugate vaccines offer the opportunity to prevent a disease that places a significant burden on an individual's health, as well as a country's public health resources. However, their implementation must be considered in the context of the epidemiological features of S. pneumoniae in each country. This paper presents the most comprehensive and detailed epidemiology of IPD in the UK to date. It raises issues of both biological and public health importance, particularly in light of the licensure of the 7-valent pneumococcal conjugate vaccine in the United States. This and higher valency vaccines are a part of the future of health in the UK, and policy decisions need to be made on the basis of such epidemiological evidence.

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Oxford Pneumococcal Surveillance Group

Members of the Oxford Pneumococcal Surveillance Group are Ian Bowler, Ros Cox, Betty Coles, Lorraine Fitch, Paul Gillette, Sharon Peacock, Mike Severn, Andrew Stacey, David Waghorn, Pat Burden, Birin Das, Mary Faiers, Anthea Coverdale, Chris Hall, Mike McIntyre, Albert Lessing, J. O'Driscoll, Mary Lyons, Lorna Willocks, and Dick Mayon-White.

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Acknowledgments

We thank the staff of the Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre, the PHLS, and the Oxford Pneumococcal Surveillance Group for data on notifications and on laboratory-diagnosed pneumococcal infections in England, Wales, and the Oxford region.

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Footnotes

  • ↵a Members of the Oxford Pneumococcal Surveillance Group are listed after the text.

  • Financial support: Public Health Laboratory Service; University Department of Paediatrics, Oxford, which is funded in part by Aventis Pasteur (to Oxford Vaccine Group).

  • Received June 22, 2000.
  • Revision received September 13, 2000.
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  1. J Infect Dis. (2001) 183 (2): 239-246. doi: 10.1086/317924
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