Increased Invasive Pneumococcal Disease, North East England, UK

Since April 2014, invasive pneumococcal disease incidence has increased substantially across North East England, United Kingdom, reversing the decline that followed the 2006 introduction of pneumococcal conjugate vaccines. Significant increases occurred in 23-valent polysaccharide vaccine serotypes and nonvaccine serotypes. Trends in other regions and long-term effects of multivalent vaccines require further investigation.


The Study
In April 2006, the NEE Invasive Pneumococcal Disease Enhanced Surveillance System was established (4) and gathered data from microbiology services, hospitals and primary care clinicians, and the Public Health England Respiratory and Vaccine Preventable Bacteria Reference Unit (9). We compared IPD incidence during the 2015/2016 epidemiologic year with that from previous epidemiologic years and with the average annual incidence during the 3 epidemiologic years covering April 1, 2011-March 31, 2014. We analyzed IPD incidence across all cases combined and cases stratified by vaccine serotype subgroups: PCV7/PCV13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F); PPV23exclusive serotypes (2, 8, 9N, 10A, 11A, 12F, 15B [including 15B/C], 17F, 20, 22F, 33F); and NVT serotypes (1). We examined IPD incidence trends by specific serotype during April 2013-March 2016 by using incidence rate ratios (IRRs), estimated by using negative binomial regression (with counts per calendar quarter, robust standard errors, and offset with the natural logarithm of the NEE population [10] Figure 2). This trend was observed among patients 5-64 and >65 years of age; cases among patients <5 years of age were considerably fewer, and temporal changes by serotype were difficult to interpret (data not shown).  Figure 2). For 23A, this increase was particularly notable among persons >65 years of age; for serotypes 15A and 35F, the increase was among persons 5-64 and >65 years of age (data not shown).

Conclusions
Total IPD incidence increased significantly, starting in 2014/2015, reversing the declines in total IPD incidence that followed the introduction of PCVs (4-8). The increases were significant for PPV23-exclusive serotypes 8, 9N, and 12F and for NVT serotypes 15A, 23A, and 35F, most notably among persons 5-64 and >65 years of age. We know of no mechanism for increased host susceptibility that could explain these rapid incidence changes. Although associations between influenza and IPD have been reported (11,12) and genetically drifted influenza strains contributed to low vaccine effectiveness in the United Kingdom during 2014/2015 (13), our primary analysis compared 2015/2016 with 2011-2014 so that any IPD increase associated with the 2014-2015 influenza season had no influence on these findings.
Mechanisms for changes in serotype prevalence include serotype replacement and capsular switching (genetic serotype switch in individual organisms) (14). In NEE, serotype replacement and declining IPD incidence were observed among persons of all age groups soon after introduction of PCV7 childhood vaccination (4), highlighting the influence of strains affecting young children in determining prevalent pneumococcal serotypes among persons in nonvaccine age groups. With ongoing >95% vaccination coverage in NEE, direct protection extends into an ever-increasing proportion of the population, up to those 10 years of age in 2016, increasing pressure on PCV strains. This pressure may be leading to accelerated serotype replacement throughout the population or to increased capsular switching, resulting in some non-PCV serotypes becoming more prevalent. Natural fluctuations in serotype prevalence may also be occurring. However, explanations for the recent IPD increase need to account for the recent and somewhat sudden rise following a long period of decline. For instance, perhaps natural expansion of non-PCV strains into the ecologic niches created has been delayed and therefore the decline observed was only temporary, or perhaps there have been recent changes in invasiveness of the non-PCV strains either naturally or associated with serotype replacement or capsular switching.
Our findings, together with data from all England (15), suggest that IPD epidemiology continues to evolve after 10 years of routine childhood vaccination. Observations from other regions that have introduced PCV are merited to determine whether the increase observed in NEE is, or becomes, a widespread phenomenon and, if so, its relationship to the timing of PCV implementation and PCV coverage. Also needed are further studies of the effects of ongoing vaccination on carriage and molecular studies to identify evidence for capsular switching and changes in invasiveness. Clarification of such factors may help guide changes to public health strategies required to tackle persistent IPD.

Acknowledgments
We thank the Public Health England North East Health Protection Team for their participation in IPD enhanced surveillance, the Public Health England Respiratory and Vaccine Preventable Bacteria Reference Unit for providing serotype results, all North East National Health Service microbiology laboratories for reporting cases of IPD, and teams from primary care and acute National Health Service trusts across NEE for providing enhanced surveillance data.