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Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis

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Summary

Background

In March 2010, 13-valent pneumococcal conjugate vaccine (PCV13) replaced the seven-valent vaccine in the USA. We assessed the effect of PCV13 use on pneumococcus-related admissions to hospital 2 years after the vaccine was introduced, when coverage in children younger than age 5 years had reached 54%.

Methods

We used data from a private inpatient discharge record database. We extracted age-specific data for admissions to hospital per month (July 1–June 30) for all-cause pneumonia, invasive pneumococcal disease, non-invasive pneumococcal pneumonia, and empyema (all coded by International Classification of Diseases 9) for 2005–12. We also extracted data for urinary tract infection and hospital admission for any reason as control outcomes. We assessed incidences of hospital admission before and after the introduction of PCV13 and used a negative binomial multiple regression model to estimate how much of the change in hospital admissions could be attributed to the vaccine.

Findings

Our model results showed that PCV13 was associated with significant reductions in hospital admissions for all-cause pneumonia for some children (21% [95% CI 14–28] in children aged <2 years, 17% [7–27] in those aged 2–4 years) and for empyema (50% [95% CI 22–68] for children age <2 years, 46% [21–64] for 2–4 years, and 37% [13–54] for 5–17 years). All-cause pneumonia was significantly reduced in adults aged 18–39 years (12% (6–17) but not for other adult age groups. The vaccine also reduced admissions for invasive pneumococcal pneumonia and non-invasive pneumococcal or lobar pneumonia in children and adults, indicating herd protection, although the reduction was only significant in some age groups.

Interpretation

Only 2 years into the US programme, PCV13 significantly reduced residual invasive and non-invasive pneumococcal hospital admissions in children younger than 5 years, as well as in some adult age groups. Our study design captured the total prevented hospital burden (directly and indirectly by herd protection) and also showed a reversal of the PCV7 era increase in paediatric empyema related to strain replacement.

Funding

Pfizer.

Introduction

The addition of the seven-valent pneumococcal conjugate vaccine (PCV7) to the USA's standard infant vaccination schedule in 2000 was a major public health milestone. Longitudinal observational studies1, 2 showed that invasive pneumococcal disease in young children caused by vaccine serotypes fell substantially soon after the vaccine was introduced. An analysis3 of Nationwide Inpatient Sample data—which covers roughly 20% of inpatients in the USA, maintained by the Agency for Healthcare Research and Quality—showed similar vaccine-associated reductions for the number of infants admitted to hospital for all causes of pneumonia as early as 2004. Admissions to hospital for invasive pneumococcal disease and pneumococcal pneumonia in adults also fell substantially by the 2003–04 season,4 as did admissions for both invasive pneumococcal disease and pneumococcal or lobar pneumonia across all age groups.4 Because these diseases are more common in people older than 65 years, about 90% of the cases prevented were judged to have been in adults even though it was the children who were immunised, showing the effect of herd protection.4

Despite the large fall in disease caused by vaccine serotypes after PCV7 was introduced, disease caused by non-vaccine serotypes soon began to increase.5, 6 For example, sharp decreases in invasive pneumococcal disease caused by PCV7 serotypes were offset by increases of disease caused by replacement serotypes—mostly 19A—leaving the overall incidence stable since around 2005, at roughly 20% of the pre-PCV7 incidence.2 Serotype 19A is associated with widespread and high-level resistance to antimicrobial drugs in the USA5, 7, 8 and is now a major cause of difficult-to-treat ear infections.9 The prevalence of the previously unrecognised serotype 6C has also increased.10

All-cause pneumonia in children became less common soon after the introduction of PCV7 and then plateaued,11 but rates of empyema increased during the 2000s in children of all ages.12 Although most of this increase was attributed to nonspecific empyema,12 many cases of empyema in children younger than age 5 years are caused by pneumococcus, particularly the non-PCV7 serotypes 1, 3, 7F, and 19A.13 Surveillance and observational studies cannot rule out the role of chance in serotype replacement, but one randomised controlled trial has linked PCV7 vaccination with 19A replacement in young children.14

Concern about serotype replacement motivated the development of PCV13, which included six additional pneumococcal serotypes: 1, 3, 5, 7F, 19A, and 6A (which induces protective antibodies against serotype 6C).15 The introduction of PCV13 in the USA in March 2010 came with a recommendation for catch-up immunisation of all children aged up to 5 years, including those previously immunised with PCV7.16

Early evidence about the effect of PCV13 on hospital admissions related to pneumococcal infection in the USA would help inform other countries considering the addition of PCV13 to their routine vaccination schedules. However, data from the US Agency for Healthcare Research and Quality are only available after a delay of at least 2 years. We have therefore used a large private database where data become available after 2 months to make an early assessment of the effect of the introduction of PCV13.

Section snippets

Study design and data sources

We did this retrospective time series analysis with data from the IMS Charge Data Master hospital database (IMS Health, Plymouth Meeting, PA, USA). This database contains deidentified data for discharge diagnoses coded by International Classification of Diseases 9 (ICD9).17 Data are taken from a convenience sample of roughly 500 non-federal, short-stay US hospitals (federally operated facilities, including Veteran's Association hospitals, are excluded), capturing roughly 20% of all admissions

Results

Figure 2 shows unadjusted trends in hospital admission rates before and after the introduction of PCV13. Decreases for 2011–12 are generally greater than those noted for 2010–11, suggesting a dose-response effect.

The unadjusted rates of hospital admission for invasive pulmonary disease and non-invasive pneumococcal or lobar pneumonia fell for all age groups between baseline and the 2011–12 season, 2 years after the programme began (table 1). However, few cases of pneumonia (1–6%) were coded

Discussion

Our findings suggest that after only 2 years, PCV13 significantly reduced hospital admissions for residual invasive and non-invasive pneumococcal pneumonia in both children and adults. Assessment of the benefit of pneumococcal vaccines for the total population is difficult in post-licensure studies, partly because much of the benefit results from herd protection of unvaccinated adults.2, 4 Case-control and prospective cohort studies can measure direct benefits, but cannot assess indirect (herd)

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