Potential Impact of Higher-Valency Pneumococcal Conjugate Vaccines Among Adults in Different Localities in Germany.

Next-generation pneumococcal conjugate vaccines (PCVs) have been approved for use. The serotype distribution of pneumococcal isolates can vary between regions. To understand the potential impacts of new PCVs, we evaluated trends in invasive pneumococcal disease (IPD) among adults in Germany at a local level using Bayesian hierarchical logistic regression. There was little spatial variation in IPD cases caused by PCV13 serotypes, which dropped from 60% of IPD cases in 2006 to 30% in 2018. Over half of IPD cases in 2018 were attributable to serotypes covered by new PCVs (PCV15, PCV20), which suggests they could further reduce the burden of IPD.

Reemergence of Invasive Pneumococcal Disease in Germany During the Spring and Summer of 2021.

BACKGROUND: The incidence of invasive pneumococcal disease (IPD) decreased worldwide in 2020 and the first quarter of 2021, concurrent with nonpharmaceutical interventions (NPIs) intended to stymie transmission of SARS-CoV-2. In 2021, the stringency of these NPI strategies has varied. We investigated age- and serotype-specific variations in IPD case counts in Germany in 2020-2021. METHODS: IPD cases through 30 November 2021 were stratified by age group, serotype, or geographic location. IPD surveillance data in 2020-2021 were compared with (1) IPD surveillance data from 2015-2019, (2) mobility data during 2020 and 2021, and (3) NPI stringency data in 2020 and 2021. RESULTS: IPD incidence began to return toward baseline among children 0-4 years old in April 2021 and exceeded baseline by June 2021 (a 9% increase over the average monthly values for 2015-2019). Children aged 5-14 years and adults aged 15-34 or ≥80 years showed increases in IPD cases that exceeded baseline values starting in July 2021, with increases also starting in spring 2021. The age distribution and proportion of vaccine-serotype IPD remained comparable to those in previous years, despite lower overall case counts in 2020 and 2021. The percentage change in IPD incidence compared with the previous 5 years was correlated with changes in mobility and with NPI stringency. CONCLUSIONS: IPD levels began to return to and exceed seasonal levels in spring and summer 2021 in Germany, following sharp declines in 2020 that coincided with NPIs related to the coronavirus disease 2019 pandemic. Proportions of vaccine serotypes remained largely consistent throughout 2020-2021.

The Impact of Changes in Diagnostic Testing Practices on Estimates of COVID-19 Transmission in the United States.

Estimates of the reproductive number for novel pathogens, such as severe acute respiratory syndrome coronavirus 2, are essential for understanding the potential trajectory of epidemics and the levels of intervention that are needed to bring the epidemics under control. However, most methods for estimating the basic reproductive number (R0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explored the impact of secular changes in diagnostic testing and reporting on estimates of R0 and Rt using simulated data. We then compared these patterns to data on reported cases of coronavirus disease 2019 and testing practices from different states in the United States from March 4, 2020, to August 30, 2020. We found that changes in testing practices and delays in reporting can result in biased estimates of R0 and Rt. Examination of changes in the daily numbers of tests conducted and the percentages of patients who tested positive might be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of coronavirus disease.

Invasive Pneumococcal Disease in Refugee Children, Germany.

Refugee children in Germany are not routinely given a pneumococcal conjugate vaccine. Cases of invasive pneumococcal disease (IPD) in 21 refugee children were compared with those in 405 Germany-born children for 3 pneumococcal seasons. Refugee children had significantly higher odds of vaccine-type IPD and multidrug-resistant IPD than did Germany-born children.

Increase of serotypes 15A and 23B in IPD in Germany in the PCV13 vaccination era.

BACKGROUND: This study presents an analysis of 1,491 serogroup 23 and 762 serogroup 15 isolates from invasive pneumococcal disease (IPD) in children and adults before and after the general recommendation for childhood pneumococcal conjugate vaccination in Germany in July 2006. Vaccination formulations used were PCV7 (from July 2006), PCV10 (from April 2009) and PCV13 (from December 2009, replacing PCV7). METHODS: The German National Reference Center for Streptococci (GNRCS) has conducted surveillance of IPD since 1992. Isolates were serotyped and tested for antibiotic susceptibility. Selected isolates were characterized using MLST. RESULTS: In an analysis of 23,957 isolates from IPD in children and adults sent to the GNRCS between July 1992 and June 2014, we found a strongly significant increase of non-PCV13 serotypes in the late vaccination (PCV13) period (2010-2014). Among these, the proportions of serotypes 15A and 23B were the most strongly significantly increasing. After the recommendation for pneumococcal conjugate childhood vaccination in 2006 and the introduction of higher-valent vaccines in 2009, the proportion of 15A increased significantly from 0.5% in the early vaccination period (2007-2010) to 2.4% in the late vaccination period (2010-2014, p=3.14 x 10(-22)). The proportion of serotype 23B increased from 0.5% to 2.8% in the same period (p=1.55 x 10(-29)). Penicillin non-susceptibility levels of the serotype 15A (47.4%) and serotype 23B (46.5%) isolates were high, with MIC values ranging from 0.12-2 µg/ml (15A) and 0.12-0.5 µg/ml (23B). MLSTs of serotype 23B isolates grouped in two clonal complexes (CC): CC439, with sequence type (ST) 439 as the main representative and CC338 (linked to CC156), with ST1349 as most prevalent clone. Both CCs have been present over almost the whole surveillance period. All penicillin non-susceptible isolates occurred in CC338. Serotype 15A isolates appeared to be more diverse. Six CCs, one group of three STs and two singletons were found among 20 isolates. Most prevalent was CC63, with ST63 as most prominent representative (n=5). Most penicillin non-susceptible isolates were found among CC63 isolates. CONCLUSIONS: The prevalence of non-PCV13 serotypes in Germany has increased significantly between July 2007 and June 2014, with 15A and 23B being the most strongly increasing serotypes of all. Both serotypes show a high proportion of penicillin non-susceptibility.

Pneumococcal meningitis and vaccine effects in the era of conjugate vaccination: results of 20 years of nationwide surveillance in Germany.

BACKGROUND: Long-term complications and a case mortality rate of 7.5% make meningitis caused by Streptococcus pneumoniae a serious clinical threat. In 2006, a general pneumococcal conjugate vaccination (PCV) recommendation was issued for all children under 2 years in Germany. Here, we investigate serotype changes in meningitis cases after this vaccine recommendation. METHODS: The German National Reference Center for Streptococci (NRCS) has conducted surveillance for invasive pneumococcal disease (IPD) in Germany since 1992. Pneumococcal isolates were serotyped by the Neufeld's Quellung reaction and antibiotic susceptibility was tested using the broth microdilution method. RESULTS: Of 22,204 IPD isolates sent to the NRCS from July 1992 to June 2013, 3,086 were meningitis cases. Microbiological and statistical investigations were performed to characterize and quantify all meningitis cases, focusing on changes reflecting implementation of the national PCV recommendation. 1,766 isolates (57.2% of meningitis cases) were from adults (≥16 years) and 1,320 isolates (42.8%) originated from children (<16 years). Overall, the leading serotypes were 14 (9.7%), 7F (7.8%), 3 (6.9%), 19F (5.7%) and 23F (5.0%). Among children, serotypes 14 (16.2%), 7F (8.9%) and 19F (7.1%) were most common, whereas among adults, serotypes 3 (9.6%), 7F (6.9%), 22F (5.0%), 23F (4.9%) and 14 (4.8%) were most prevalent. After the introduction of general PCV7/10/13 vaccination a significant decrease for most vaccine serotypes was observed. Generally, the differences in antibiotic nonsusceptibility between children <16 years and adults ≥16 were low. For macrolides in the pre-PCV7 period, a significantly higher proportion of resistant isolates was found in children (25.1%), compared to the post-vaccination period (9.7%; p<0.0001). CONCLUSIONS: Implementation of the pneumococcal conjugate vaccines broadly reduced vaccine-type meningitis cases. Changes in serotype prevalence must be continuously monitored to observe future trends concerning pneumococcal meningitis.

Worldwide Index of Serotype-Specific Pneumococcal Antibody Responses (WISSPAR): A curated database of clinical trial data.

The Worldwide Index of Serotype Specific Pneumococcal Antibody Responses (WISSPAR; https://wisspar.com), is a centralized, online platform housing data on immunogenicity from clinical trials of pneumococcal vaccines. The data on WISSPAR are primarily curated from outcomes tables from clinical trials and are made available in a searchable format that can be readily used for downstream analyses. The WISSPAR database includes trials covering numerous vaccine products, manufacturers, dosing schedules, age groups, immunocompromised groups, and geographic regions. Customizable data visualization tools are embedded within the site, or the data can be exported for further analyses. Users can also browse summary information about the clinical trials and their results. WISSPAR provides a platform for analysts and policy makers to efficiently gather, compare, and collate clinical trial data about pneumococcal vaccines.

The potential of saliva as an accessible and sensitive sample type for the detection of respiratory pathogens and host immunity.

Despite its prominence in early scientific records, the usefulness of saliva as a respiratory specimen has been de-emphasised over the past century. However, due to its low cost and reliance on specific supply chains and the non-invasive nature of its collection, its benefits over swab-based specimens are again becoming increasingly recognised. These benefits were highlighted over the course of the COVID-19 pandemic, where saliva emerged as a more practical, clinically non-inferior sample type for the detection of SARS-CoV-2 and saw numerous saliva-based diagnostic tests approved for clinical use. Looking forward, as saliva uniquely contains both respiratory secretions and immunological components, it has potentially wide applications, ranging from clinical diagnostics to post-vaccine disease burden and immunity surveillance. This Personal View seeks to summarise the existing evidence for the use of saliva in detecting respiratory pathogens, beyond SARS-CoV-2, as well as detailing methodological factors that can influence sample quality and thus, clinical utility.

Correction to "Pneumococcal vaccine uptake and vaccine effectiveness in older adults with invasive pneumococcal disease in Germany: A retrospective cohort study".

[This corrects the article DOI: 10.1016/j.lanepe.2021.100126.].

50 policies, 1 pandemic, 500,000 deaths: Associations between state-level COVID-19 testing recommendations, tests per capita, undercounted deaths, vaccination policies, and doses per capita in the United States.

BACKGROUND: State health departments have been responsible for prioritizing and allocating SARS-CoV-2 tests and vaccines. Testing and vaccination recommendations in the United States varied by state and over time, as did vaccine rollouts, COVID-19 cases, and estimates of excess mortality. METHODS: We compiled data about COVID-19 testing, cases, and deaths, and excess pneumonia + influenza + COVID-19 deaths to assess relationships between testing recommendations, per capita tests performed, epidemic intensity, and excess mortality during the early months of the COVID-19 pandemic in the United States. We compiled further data about state-level SARS-CoV-2 vaccination policies and doses administered during the early months of the vaccine rollout. RESULTS: As of July 2020, 16 states recommended testing asymptomatic members of the general public. The rate of COVID-19 tests reported in each state correlated with more inclusive testing recommendations and with higher epidemic intensity. Higher per capita testing was associated with more complete reporting of COVID-19 deaths, which is a fundamental requirement for analyzing the pandemic. Testing per capita during the first three months was associated with vaccination per capita in the first three months of rollout. Per capita vaccine doses in each state were not associated with adherence to national guidelines. CONCLUSIONS: Reported deaths due to COVID-19 likely represent an undercount of the true burden of the pandemic. States that struggled with testing rollout have also frequently struggled with vaccine rollout. Coordinated, consistent guidelines for COVID-19 testing and vaccine administration should be a high priority for state and national health systems.

Pneumococcal vaccine uptake and vaccine effectiveness in older adults with invasive pneumococcal disease in Germany: A retrospective cohort study.

BACKGROUND: Invasive pneumococcal disease (IPD) in people ≥60 years old is on the rise in Germany. There has been a recommendation for pneumococcal vaccination in this age group since 1998. METHODS: We determined the vaccination status of people ≥60 years old with IPD in Germany. We assessed vaccine effectiveness (VE) of the recommended 23-valent polysaccharide vaccine (PPV23) against IPD using the indirect cohort method. RESULTS: The rate of pneumococcal vaccination in older adults with IPD is low, 26%, with only 16% of people receiving a pneumococcal vaccine within five years of the IPD episode. Age- and gender- adjusted vaccine effectiveness (VE) for PPV23 was 37% (95% confidence interval 12% - 55%). For people vaccinated with PPV23 less than two years prior to IPD, VE was -20% (-131% - 34%), between two and four years prior to IPD, VE was 56% (20% - 76%), and 47% (17% - 63%) for those vaccinated ≥5 five years ago. Excluding serotype 3, overall VE for the remaining serotypes in PPV23 was 63% (49% - 74%). For people receiving PPV23 within the past two years, VE against all serotypes except 3 was 49% (12% - 71%); for people vaccinated between two and four years prior to IPD 66% (37% - 82%); for those vaccinated ≥five years ago, 69% (50% - 81%). VE of PPV23 against serotype 3 IPD only was -110% (-198% - -47%). CONCLUSIONS: To reduce IPD in older adults in Germany, we must increase the rate of pneumococcal vaccine uptake. For 22/23 serotypes, PPV23 was effective. Serotype 3 remains a major problem. FUNDING: This work was supported by an investigator-initiated research grant from Pfizer.

Bacterial Spectrum of Spontaneously Ruptured Otitis Media in a 7-Year, Longitudinal, Multicenter, Epidemiological Cross-Sectional Study in Germany.

We analyzed middle ear fluid (MEF) and nasopharyngeal swabs (NPS) from spontaneously ruptured acute otitis media (AOM) cases occurring in children under 5 years in Germany. The aim of the study was the assessment of disease burden and bacterial etiology in the era of routine pneumococcal vaccination. Furthermore, we aimed to compare isolates from MEF with isolates from NPS and to analyze the Streptococcus pneumoniae serotype distribution. We analyzed MEF and NPS samples in children 2 months to 5 years for vaccination status, frequency of bacterial strains, serotype/emm-type distribution of S. pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes; and intraindividual correlation between MEF and NPS. From 2008 to 2014, MEF samples were collected from 2,138 subjects of which 2,001 (93.6%) also provided an NPS sample. In 851 of 2,138 MEF samples (39.8%), we identified organisms with confirmed pathogenic potential-S. pyogenes: 315 (14.7%), S. pneumoniae: 170 (8.0%), Staphylococcus aureus: 168 (7.9%), H. influenzae: 133 (6.2%), and Moraxella catarrhalis. Among NPS samples, 1,018 (50.9%) contained S. pneumoniae, 775 (38.7%) H. influenzae, 648 (32.4%) M. catarrhalis, and 344 (17.2%) S. pyogenes. Over the seven study years, the number of AOM patients steadily decreased, while the recruiting base remained constant. S. pneumoniae MEF isolates decreased by 86%, with serotype 3 being the most prevalent (25.7-42.9%). PCV13-non-PCV7-non-3 serotypes reduced to 0%. Among NPS, PCV7 serotypes decreased from 14.1 to 3.7%, PCV10: 17.6 to 3.7%, and PCV13: 55.3 to 25.7%. PCV13-non-PCV7-non-3 serotypes increased in the first 3 years of the study (17.1-22.9%), then decreased to 4.6% in year 7. Non-typeable H. influenzae reduced from 87.1 to 41.7% in MEF and from 91.4 to 54.2% in NPS. MEF and NPS isolates from the same subject were identical for 91.9% of S. pneumoniae, 99.0% of S. pyogenes, and 83.3% of H. influenzae. Among PCV7-vaccinated children, 5.6% had a PCV7 vaccine type in the MEF sample, and among PCV13-vaccinated children, 51.7% had a PCV13 serotype. Among non-vaccinated children, the percentages were 14.8 and 70.4. Pneumococcal conjugate vaccination has impacted the prevalence and etiology of spontaneously ruptured otitis media among children in Germany. Overall case numbers and pneumococcal vaccine type cases have strongly decreased.

Correction: Limited indirect effects of an infant pneumococcal vaccination program in an aging population.

[This corrects the article DOI: 10.1371/journal.pone.0220453.].

The impact of changes in diagnostic testing practices on estimates of COVID-19 transmission in the United States.

Estimates of the reproductive number for novel pathogens such as SARS-CoV-2 are essential for understanding the potential trajectory of the epidemic and the level of intervention that is needed to bring the epidemic under control. However, most methods for estimating the basic reproductive number (R0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explore the impact of secular changes in diagnostic testing and reporting on estimates of R0 and Rt using simulated data. We then compare these patterns to data on reported cases of COVID-19 and testing practices from different United States (US) states. We find that changes in testing practices and delays in reporting can result in biased estimates of R0 and Rt. Examination of changes in the daily number of tests conducted and the percent of patients testing positive may be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of COVID-19.

Limited indirect effects of an infant pneumococcal vaccination program in an aging population.

BACKGROUND: A general recommendation for adult pneumococcal vaccination with 23-valent polysaccharide vaccine (PPV23) for adults 60 and older has been in place in Germany since 1998, but uptake has been low. Just over a decade after the implementation of an infant pneumococcal conjugate vaccine recommendation, we examined indirect protection effects on adult invasive pneumococcal disease (IPD) in Germany. METHODS AND FINDINGS: Reported IPD cases decreased in children under two years of age from 11.09 per 100,000 in 2003-2006 to 5.94 per 100,000 in 2017/18, while in adult age groups, reported IPD cases rose across the board, most dramatically in adults 60 years of age and over, from 1.64 to 10.08 cases per 100,000. PCV13-type IPD represents 31% of all cases in this age group, the lion's share of which is due to the rapid increase of serotype 3 IPD, which, by itself, has reached 2.11 reported cases per 100,000 and makes up 21% of all IPD cases in this age group. The two vaccine formulations currently in development (PCV15 and PCV20) would increase current (PCV13) coverage by 8.5% points and 28.0% points in children, while in adults coverage would increase by 10.4% points and 21.9% points, respectively. CONCLUSIONS: While original models predicted that indirect effects of childhood vaccination would suffice for adults, it seems that the herd protection effect has reached its limit, with vaccine serotypes 4, 19F, and 19A IPD persisting in adults after initial reductions, and serotype 3 IPD not showing any herd protection effect at all.

Regional variations in serotype distribution and vaccination status in children under six years of age with invasive pneumococcal disease in Germany.

OVERVIEW: The protective effect of infant pneumococcal conjugate vaccine (PCV) recommendation can be seen in Germany as a whole and in smaller regional groups. Comparisons between population-normalized geographic regions of Germany show different serotype distributions after program implementation, particularly in non-vaccine serotypes. The prior distinct differences in serotype distribution in children between the former East and former West German federal states have vanished. Children under six remain a vulnerable group, but the occurrence of vaccine-type (VT) invasive pneumococcal disease (IPD) in children correctly vaccinated (using a three-dose primary series plus one booster dose) with PCV13 was low (9 out of 374 cases, 2.4%). However, only 18.4% of children in Germany with IPD were correctly vaccinated with PCV13 according to the recommended schedule. Continued surveillance and better schedule adherence are essential to definitively establish the most effective PCV administration schedule. VACCINATION EFFECTS: For all PCV products used in Germany (PCV7, PCV10, and PCV13), vaccination status was the most common statistically significant predictor of infection with a particular serotype: Unvaccinated children old enough to have received at least one dose of vaccine in the PCV7 group had significantly higher odds (OR: 6.84, 95%CI: 2.66-22.06, adjusted for per capita income and residence in the northeastern federal states) of contracting VT IPD. In the PCV10 group, VT IPD had an OR of 4.52 (95% CI: 1.60-15.62, adjusted for year of infection, median household size, and residence in the southern federal states) in unvaccinated children, and in the PCV13 group, unvaccinated children continued to have higher odds (OR: 6.21, 95%CI: 3.45-11.36, adjusted for year of infection, age of child, per capita income, residence in the southern federal states, and percentage of children using public daycare) of getting vaccine-type IPD. Being unvaccinated was the most frequent significant indicator for infection with vaccine-type serotypes for each analysis group, while geographic groupings showed more limited potential to predict serotype of infection in early childhood IPD in Germany.

Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014.

A nationwide laboratory-based surveillance study of invasive S. pyogenes infections was conducted in Germany. Invasive isolates (n = 719) were obtained between 2009 and 2014. Most isolates were obtained from blood (92.1%). The proportions of isolates from cerebrospinal fluid, pleural fluid, synovial fluid and peritoneal fluid were 3.9%, 1.8%, 1.7% and 0.6%, respectively. The most common emm types were emm 1 (31.8%), emm 28 (15.4%) and emm 89 (14.5%). The most common superantigen genes (speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa) identified from S. pyogenes were speG (92.1%), speJ (50.9%), and speC (42.0%). Significant associations of superantigen genes with underlying conditions or risks were observed in speG, speH, speJ, and speK. Significant associations between emm types or superantigen genes with clinical complications were observed in emm type 3 and in superantigen gene speA 1-3. Most frequent clinical manifestations included sepsis 59.4%, STSS 6.3%, meningitis 5.4%, and necrotizing fasciitis 5.0% (significantly associated with emm1).

Effectiveness of Pneumococcal Conjugate Vaccines (PCV7 and PCV13) against Invasive Pneumococcal Disease among Children under Two Years of Age in Germany.

BACKGROUND: In this study we calculate the effectiveness of pneumococcal conjugate vaccines (PCV) against invasive pneumococcal disease (IPD) among children under the age of two years using the indirect cohort method. We also discuss the timeliness of vaccination and the residual cases of vaccine type IPD. METHODS AND FINDINGS: From July 2006 until June 2015, 921 IPD cases were reported and for 618 children (67.1%), the vaccination status at the time of infection could be accurately determined. Of these, 379 (61.3%) were vaccinated and 239 (38.7%) were not vaccinated. The adjusted vaccine effectiveness (VE) of PCV7 for all included serotypes + 6A was 80% (95% CI: 63-89) for at least one dose, 97% (89-100) after three primary doses (post primary) and 95% (57-100) post booster. The adjusted overall VE of PCV13 was 86% (74-93) for at least one dose, 85% (62-94) post primary and 91% (61-99) post booster. For the additional serotypes included in PCV13, the adjusted VE was 82% (66-91), 80% (46-93) and 90% (54-98) respectively. The serotype specific VE for at least one dose was high for serotypes 1 (83%; 15-97), 3 (74%; 2-93), 7F (84%; 18-98) and 19A (77%; 47-90). Only 39.5% of children with IPD obtained their first dose of PCV7 according to schedule (2nd dose: 32.9%, 3rd dose: 22.0%, booster dose: 63.6%). For children vaccinated with PCV13 values were slightly better: 43.8%, 33.5%, 26.3% and 74.3% respectively. Among 90 residual cases with PCV7 serotypes, 73 (81.1%) were in unvaccinated children, and 15 (16.7%) in children who had not obtained the number of doses recommended for their age, and only two (2.2%) in children vaccinated according to age. Of 82 cases with PCV13 serotypes occurring after the switch from PCV7 to PCV13, 56 (68.3%) were not vaccinated, 22 (26.8%) were incompletely vaccinated, and four (4.9%) were vaccinated according to age. CONCLUSIONS: Our data show a high effectiveness of pneumococcal conjugate vaccination in Germany. However, the administration of vaccine doses among children with IPD is often delayed, resulting in many vaccine type cases in non- or incompletely-vaccinated children. Whether the recently-implemented change to a 2+1 schedule will improve the timeliness of vaccination should be subject to careful monitoring.

Effects of Infant Pneumococcal Conjugate Vaccination on Serotype Distribution in Invasive Pneumococcal Disease among Children and Adults in Germany.

This study describes the effects of the introduction of universal infant pneumococcal conjugate vaccination in 2006 on invasive pneumococcal disease (IPD) among children and adults in Germany with a focus on the dynamics of serotype distribution in vaccinated and non-vaccinated age groups. Over a period of 22 years (1992-2014), microbiological diagnostic laboratories from all over Germany have been sending isolates of IPD cases to the German National Reference Center for Streptococci on a voluntary basis. Streptococcus pneumoniae isolates were serotyped using Neufeld's Quellung method. Among children <16 years, the proportion of PCV7 serotypes among isolates from IPD cases decreased from 61.8% before vaccination (1997-2006) to 23.5% in the early vaccination period (2007-2010; p = 1.30E-72) and sank further to 5.2% in the late vaccination period (2010-2014; p = 4.59E-25). Similar reductions were seen for the separate age groups <2 years, 2-4 years and 5-15 years. Among adults, the proportion of PCV7 serotypes decreased from 43.4% in the pre-vaccination period (1992-2006) to 24.7% (p = 3.78E-88) in the early vaccination period and 8.2% (p = 5.97E-161) in the late vaccination period. Both among children and among adults, the non-PCV7 serotypes 1, 3, 7F and 19A significantly increased in the early vaccination period. After the switch from PCV7 to PVC10/PCV13 for infant vaccination in 2010, serotypes 1, 6A and 7F significantly decreased. A decrease in serotype 19A was only observed in 2013-2014, as compared to 2010-2011 (children p = 4.16E-04, adults p = 6.98E-06). Among adults, serotype 3, which strongly increased in the early vaccination period (p = 4.44E-15), remained at a constant proportion in the late vaccination period. The proportion of non-PCV13 vaccine serotypes increased over the whole vaccination period, with serotypes 10A, 12F, 23B, 24F and 38 most significantly increasing among children and serotypes 6C, 12F, 15A, 22F and 23B increasing among adults. Eight years of childhood pneumococcal conjugate vaccination have had a strong effect on the pneumococcal population in Germany, both among the target group for vaccination as well as among older children and adults.