During 2006–2022, we identified 3,719 adults (median age 66.1 years, interquartile range 50.2–78.9 years) who had pneumococcal disease. Of those persons, 1,840 (49.5%) were male, 1,879 (50.5%) were female, 1,621 (43.6%) had positive blood cultures, 2,379 (64.0%) were UAT positive, and 15 (0.4%) were PCR positive. Among the cases, 1,686 (45.3%) were IPD and 2,033 (54.7%) were non-IPD. Respiratory infection accounted for 92.3% (3,436/3,719) of all cases of pneumococcal disease, 84.2% of IPD, and 99.2% of noninvasive pneumococcal disease (Table 1). Pneumococcal serotype was available for 1,501 (40%) cases. The demographics and clinical characteristics of patients with known-serotype pneumococcal disease were similar to those with unknown serotype infection (Appendix).

The incidence of IPD among hospitalized adults showed a slight upward trend during 2006‒late 2019 (Figure 1, panel A). During the early part of the COVID-19 pandemic in 2020, pneumococcal disease incidence suddenly decreased. However, during 2022, incidence gradually increased so that by December 2022 it had returned to a level similar to that observed before the COVID-19 pandemic (Figure 1, panel A). Noninvasive pneumococcal disease showed a broadly similar pattern but is harder to interpret because of changing BinaxNOW testing patterns over the study period (Figure 1, panel C; Appendix Figures 3, 4). PCV7 serotype disease decreased from 29.4% (95% CI 24.1%–35.4%) in 2006–2009 to 7.0% (95% CI 3.7%–12.7%) of serotype-known disease in 2021–2022, and PCV7-serotypes caused minimal disease from mid-2017 until their re-emergence during the COVID-19 pandemic. PCV13–7 disease represented 34.3% (95% CI 28.6%–40.4%) of serotype-known disease in 2006–2009, decreased slightly to 29.3% (95% CI 25.6%–33.3%) by 2010–2015, and continued to decrease to 21.7% (95% CI 15.5%–29.6%) in 2021–2022, with serotypes 1, 3, and 19A persisting. In contrast, the percentage of PCV20–13 and non-PCV serotype disease increased during this period (Figure 1, panel B).

Although blood culture testing rates remained stable over time, there were changes in UAT testing rates. The decreased pneumococcal disease incidence observed during the COVID-19 pandemic occurred without an equivalent decrease in BinaxNOW and blood culture testing over the same time period (Figure 1, panel C). After SARS-CoV-2 emergence, the most commonly identified serotypes were 3, 8, 9N, 19F, 19A and 22F (Figure 2, panels A, B). In 2022, 6.2% (95% CI 3.2%–11.8%) of disease was attributable to PCV15–13, 33.3% (95% CI 25.8%–41.8%) to PCV20–15, and 31.8% (95% CI 24.4%–40.2%) to non-PCV serotypes; a major percentage of disease arose from serotypes in current PCVs (Figure 2). Among known-serotype cases, PCV7 serotypes represented 7.0% (95% CI 3.7%–12.7%) and PCV13–7 serotypes 21.7% (95% CI 15.5%–29.6%) of cases (Table 2). Overall, the percentage of disease caused by 19F, 19A, and 22F remained relatively stable throughout the study, and an expansion of serotypes 3 and 8 disease occurred, along with a slight increase in serotype 9N (Figure 2, panel C).

Before the emergence of SARS-CoV-2, the age of patients admitted with IPD increased over time (Figure 3, panel A) and disease severity decreased, as shown by the average CURB65 severity scores at admission (Figure 3, panel B). ICU admission rates increased in earlier years and then plateaued, inpatient deaths decreased, and length of hospital admission remained broadly stable (Figure 3, panels C‒E). Those trends were disrupted during the early stages of the SARS-CoV-2 pandemic and largely reverted to their previous trajectories in 2021–2022. The percentage of patients 45–55 years of age trended upwards compared with the prepandemic period, and the percentage of IPD case-patients requiring ICU admission also increased, but those trends were based on small numbers. We could not account for the increase in ICU admissions seen after SARS-CoV-2 emergence through change in bed availability or clinical care pathways.

This study examining hospitalized adults with pneumococcal disease in Bristol and Bath, UK, encompasses 17 years of PCV implementation into the UK childhood vaccination program and includes 3 years of the COVID-19 pandemic. Although the percentage of IPD caused by PCV serotypes has decreased across all age groups, a major fraction of adult pneumococcal disease is still caused by PCV7 (7.0% [95% CI 3.7%–12.7%]) and PCV13–7 (21.7% [95% CI 15.5%–29.6%]) serotypes (5,22). In addition, the percentage of adult disease caused by those serotypes has increased since COVID-19 pandemic restrictions began in March 2020, which also coincided with a change in the UK childhood immunization schedule from 3 doses to 2 doses of PCV13 since April 2020. The persistence of PCV13 serotype and PCV7 serotype disease in adults in this study occurred in the context of a longstanding, high-coverage national childhood vaccination program. This persistence suggests that, although giving PCVs to most children has had some indirect effects, those effects do not completely protect adults from PCV serotype disease.

The persistence of some PCV13 serotypes is concerning because they are associated with more severe disease and deaths in adults. In addition, we have observed large increases in the percentage of non-PCV13 serotype disease since PCV13 implementation, consistent with national surveillance throughout the UK and Europe (5‒7,12,22). During 2016–2019, non-PCV13 serotypes caused 78.8% (95% CI 75.2%–82.1%) of cases among persons who had identified serotypes; during 2021–2022 that percentage was 71.3% (95% CI 63.0%–78.4%). During 2021–2022, PCV20–13 serotypes accounted for 39.5% (95% CI 31.5%–48.2%) of adult disease with identified serotypes.

Despite indirect effects operating to some degree, PCV serotypes continue to cause adult disease that is severe enough to require hospital admission. Although PCV7 serotypes remain rare causes of adult pneumococcal disease, serotype 19F has reemerged. We found that most residual PCV serotype disease is caused by PCV13–7 serotypes, especially serotypes 3 and 19A, observations that are consistent with other reports (5,7,12,22). The continued circulation of serotype 3, especially after the pandemic restrictions were lifted, is critical because this serotype is associated with more severe disease, especially in older adults. Ongoing circulation might, in part, be caused by clade II expansion after a clade distribution shift (23). Serotype 19A is also of concern because it has previously been associated with high antimicrobial drug resistance rates in some countries (24).

Indirect effects of PCVs are believed to occur by reduction in nasopharyngeal carriage and density of vaccine serotypes in vaccinated children, which interrupts transmission to both vaccinated and unvaccinated contacts (2–4). Generally, sustained high PCV coverage in children is assumed to result in reliable indirect effects in adults: the UK 1 + 1 PCV13 childhood immunization schedule relies, to a degree, on those indirect effects to protect infants who only receive 1 priming PCV dose before their 1-year booster (25). However, we cannot explain the recent percentage increase in PCV13 serotype disease we observed by decreasing pediatric PCV vaccination rates. In the United Kingdom, vaccination is offered free of charge and is associated with high uptake; PCV uptake was >90% for the first dose by 12 months of age and >94% for the second dose by 24 months of age in southwestern England in 2021–2022 (26).

A concerning finding is the high percentage of cases that are not vaccine preventable: during 2016–19, PCV20–13 and non-PCV serotypes represented 53.0% (95% CI 48.8%–57.2%) and 25.8% (95% CI 22.3%–29.7%) of cases, respectively; in 2021‒2022, those percentages of 39.5% (95% CI 31.5%–48.2%) and 31.8% (95% CI 24.4%–40.2%). In 2021–22, PCV15 serotypes represented 34.9% (95% CI 27.2%–43.4%) of IPD cases, PCV20 serotypes 68.2% (95% CI 59.8%–75.6%) and non-PCV serotypes 31.8% (95% CI 24.4%–40.2%). Although serotype replacement has been observed in Europe and serotype distribution change in the United States (5–7,21,27,28), reports from the United States describe consistently stable rates of non-PCV13 serotype IPD after childhood PCV13 introduction (29). Serotype replacement might occur through expansion of non-PCV strains or capsular switching of previously vaccine-preventable strains, in which recombination at the capsular gene locus results in serotype change (30). In concordance with other studies, we found serotype 8 disease increasing, along with 23A and 9N (5,7,12).

We observed a disproportionate decrease in pneumococcal disease incidence early in the COVID-19 pandemic, without a concomitant decrease in BinaxNOW and blood culture testing rates. This finding might have been caused by reduced circulation and transmission of many respiratory pathogens, including pneumococcus, because of social distancing policies (13,14,16) breaking transmission chains and affecting host‒pathogen‒pathogen interactions, so that severe pneumococcal infection became less common. Preceding viral infection is a major risk factor for pneumonia, and the relationships between influenza and respiratory syncytial virus and pneumococcus are well described (31,32). Pneumococcus might also modulate host immune responses to SARS-CoV-2 (33). Prospective surveillance found that Europe experienced major and sustained reductions in invasive disease caused by pneumococcus, Haemophilus influenzae, and Neisseria meningitidis in early 2020 (34). Our study confirms that reduced testing practices in hospitals do not explain such reductions.

However, changes in healthcare use might explain the incidence decreases that occurred. For example, susceptible patients had fewer admissions to secondary care during the pandemic (35). An increased admission threshold or avoidance of secondary care would increase community-level management of cases and reduce case-patients who have pneumococcal disease seeking treatment and consequently being diagnosed in hospitals. Because fewer investigations are performed in community-level care, such cases would be missed by surveillance that is reliant on microbiologic testing.

By combining microbiologic results with clinical data, we are able to report on both disease epidemiology and severity over time. We found some evidence of more severe disease, especially after SARS-CoV-2 emergence. The observed disruption to the broadly stable previous trends in disease severity during the early part of the SARS-CoV-2 pandemic might be a result of observation bias, a consequence of the pandemic, or both. Although ICU admission rates increased for pneumococcal disease, admission CURB65 severity scores were lower, consistent with the 2018 BTS national pneumonia audit, which also reported decreased admission CURB65 scores (36). This apparent discrepancy might be explained by changes in patients or their treatment (e.g., older patients with more severe disease might be less likely to receive ICU care than younger patients because of clinical prognostic decision making). Other recent changes in treatment, such as increased availability of positive pressure support or earlier antimicrobial drug administration, might also have changed patient courses and outcomes, including severity and death. Major changes in pneumococcal infection severity have occurred since 2020, including an increased percentage of adults 45–55 years of age who required hospital treatment. The recent increase in cases is probably related to relaxation of COVID-19 restrictions. Recent studies highlight the critical role of respiratory viruses (e.g., respiratory syncytial virus, human metapneumovirus, influenza virus) in contributing to pneumococcal disease (17). Large, out-of-season viral outbreaks that occurred after easing of COVID-19 restrictions (37) are therefore likely to have contributed to the increasing pneumococcal disease rates we report in this study, which will need careful surveillance in future years. Independent of changes in clinical practice, serotype distribution changes might affect patient outcomes and healthcare use as invasive potential varies by serotype.

By combining microbiologic results with clinical data, we are able to report on both disease epidemiology and severity over time. We found some evidence of more severe disease especially after SARS-CoV-2 emergence. The observed disruption to the broadly stable previous trends in disease severity during the early part of the SARS-CoV-2 pandemic might be a result of observation bias, a consequence of the pandemic, or both. Although ICU admission rates increased for pneumococcal disease, we observed a reduction in admission CURB65 severity scores, consistent with the 2018 BTS national pneumonia audit, which also reported decreased admission CURB65 scores (36). This apparent discrepancy might be explained by changes in patients or their treatment (e.g., older patients with more severe disease might be less likely to receive ICU care than younger patients because of clinical prognostic decision making). Other recent changes in treatment, such as increased availability of positive pressure support or earlier antimicrobial drug administration, might also have changed patient courses and outcomes, including severity and death. Major changes in pneumococcal infection severity have occurred since 2020, including an increased percentage of adults 45–55 years of age who required hospital treatment. The recent increase in cases is probably related to relaxation of COVID-19 restrictions. Recent studies highlight the critical role of respiratory viruses (e.g., respiratory syncytial virus, human metapneumovirus, influenza virus) in contributing to pneumococcal disease (17). Large, out-of-season viral outbreaks that occurred after easing of COVID-19 restrictions (37) are therefore likely to have contributed to the increasing pneumococcal disease we report in this study, which will need careful surveillance in future years. Independent of changes in clinical practice, serotype distribution changes might affect patient outcomes and healthcare use as invasive potential varies by serotype.

One strength of this study was that we identified patients who had with pneumococcal infections in a population of ≈1 million adults and report disease over a 17-year period with epidemiologic data supported by detailed clinical information at an individualized patient level. Data on admission numbers and testing practices enabled us to interpret incidence considering these factors, which might otherwise bias the estimates obtained. In addition, linkage with the UKHSA national reference laboratory enabled us to report serotype data whenever available. Our study also reports pneumococcal disease confirmed by UAT; this result was not detected by national surveillance and enabled us to estimate pneumococcal disease incidence and burden more accurately.

One limitation of this study was that UAT does not identify serotype; we were thus unable to report serotype data in 60% of our cohort. However, patients with known and unknown serotype disease had broadly similar demographic and clinical characteristics and outcomes. UAT has a sensitivity of 65%, so test results might remain positive for some time after pneumococcal disease has been treated (38). Although the data are concordant with national UKHSA epidemiologic and BTS pneumonia audit data (36), providing major reassurance, this regional study might not be representative of other regions or populations. As a retrospective observational study, only information as documented in medical records could be included. Patient treatment decisions might have varied over time and by treating physicians, and systemic changes in patient treatment, healthcare provision, or admission threshold and microbiologic testing practices might have occurred. Those factors might have affected the trends reported in this analysis. Finally, the serotype trends reported in 2020–2022 were based on substantially lower case numbers than those seen before the emergence of SARS-CoV-2. Ongoing monitoring of trends will be useful as disease incidence adjusts after the COVID-19 pandemic.

In conclusion, this study provides evidence that PCV13 serotypes continue to cause pneumococcal disease in adults, suggesting that indirect effects of the childhood PCV program might not lead to additional reductions in the residual burden of those serotypes in adults. After the COVID-19 pandemic, serotype distribution changes have resulted in an increase in adult pneumococcal disease attributable to PCV serotypes, and a major burden of current disease could be directly prevented by introducing PCV20, which has recently been licensed for adults. Ongoing surveillance of adult pneumococcal disease is vital to evaluate vaccine effect and monitor replacement disease. The extent of indirect effects of PCVs should continue to be carefully evaluated and considered in formulating future public health policy recommendations.