key: cord-0267859-twuh34ko authors: Bahrs, C.; Kesselmeier, M.; Kolditz, M.; Ewig, S.; Rohde, G.; Barten-Neiner, G.; Rupp, J.; Witzenrath, M.; Welte, T.; Pletz, M. title: A longitudinal analysis of pneumococcal vaccine serotypes in pneumonia patients in Germany date: 2021-10-07 journal: nan DOI: 10.1101/2021.10.07.21264682 sha: f7ad7c092379d89fe83a31febbc68b305b81728f doc_id: 267859 cord_uid: twuh34ko Recently, a 15-valent (PCV15) and a 20-valent pneumococcal conjugate vaccine (PCV20) have been licensed by the US Food and Drug Administration and are under evaluation by the European Medicines Agency.PCV15 contains all serotypes of the 13-valent conjugate vaccine (PCV13) plus serotype 22F and 33F and PCV20 includes PCV13 serotypes plus serotype 8, 10A, 11A, 12F, 15B, 22F and 33F. We investigated pneumococcal serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20, and the 23-valent pneumococcal polysaccharide vaccine (PPV23) among adult patients with all-cause community-acquired pneumonia (CAP) between 2013 and 2019. We applied logistic mixed regression modelling to assess annual trends. Urine samples from adult patients with CAP treated in the community or hospital in Germany and included in the CAPNETZ study, a prospective multi-centre cohort study, were analysed by two serotype-specific multiplex urinary antigen detection assays (UAD1/UAD2) at Pfizer's Vaccines Research and Development Laboratory. UAD1 detects serotypes in PCV13, UAD2 detects additional serotypes in PCV20 plus serotypes 2, 9N, 17F and 20. Out of 1,831 patients screened, urine samples with a valid UAD test result were available for 1,343 patients (73.3%). Among those patients, 829 patients (61.7%) were male, 792 patients (59,0%) were aged 60 years and above, 1038 patients (77.3%) had at least one comorbidity and 1,204 patients (89.7%) were treated in the hospital. The overall proportion of vaccine-type pneumonia among all-cause CAP for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage against pneumonia in adults (PCV13: OR 0.94, 95% CI 0.83-1.05; PCV15: OR 0.93, 95% CI 0.84-1.03; PCV20: OR 0.95, 95% CI 0.86-1.04; PPV23: OR 0.99, 95% CI 0.90-1.08). In conclusion, our data show that i) the infant vaccination program of PCV13, which started in Germany 2010 did not result in a relevant and sustained decrease of PCV13 serotypes in pneumonia in adults and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time. 12F, 15B, 22F, 33F. We investigated pneumococcal serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20, and the 23-valent pneumococcal polysaccharide vaccine (PPV23) among adult patients with all-cause community-acquired pneumonia (CAP) between 2013 and 2019. We applied logistic mixed . CC-BY 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 /2021 doi: medRxiv preprint 2 regression modelling to assess annual trends. Urine samples from adult patients with CAP treated in the community or hospital in Germany and included in the CAPNETZ study, a prospective multi-centre cohort study, were analysed by two serotype-specific multiplex urinary antigen detection assays (UAD1/UAD2) at Pfizer's Vaccines Research and Development Laboratory. UAD1 detects serotypes in PCV13, UAD2 detects additional serotypes in PCV20 plus serotypes 2, 9N, 17F and 20. Out of 1,831 patients screened, urine samples with a valid UAD test result were available for 1,343 patients (73.3%). Among those patients, 829 patients (61.7%) were male, 792 patients (59.0%) were aged 60 years, 1038 patients (77.3%) had at least one comorbidity and 1,204 patients (89.7%) were treated in the hospital. The overall proportion of vaccine-type pneumonia among all-cause CAP for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage against pneumonia in adults (PCV13: OR 0.94, 95% CI 0.83-1.05; PCV15: OR 0.93, 95% CI 0.84-1.03; PCV20: OR 0.95, 95% CI 0.86-1.04; PPV23: OR 0.99, 95% CI 0.90-1.08). In conclusion, our data show that i) the infant vaccination program of PCV13, which started in Germany 2010 did not result in a relevant and sustained decrease of PCV13 serotypes in pneumonia in adults and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time. . CC-BY 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Pneumococcal infections are globally the most frequent vaccine-preventable cause of death [1], and community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae is the main burden of pneumococcal disease in the elderly [2] . Since respiratory and blood cultures remain often negative in hospitalized patients with pneumococcal CAP due to prior antibiotic treatment, most cases are detected by the pneumococcal urinary antigen test (PUAT, BinaxNOW® S. pneumoniae) [2, 3] . As the PUAT does not allow serotype discrimination, data on serotype distribution in adult non-bacteremic pneumococcal CAP patients are sparse [4] . Pneumococcal conjugate vaccines (PCVs), which were primarily developed for vaccination of infants under 2 years of age, have significantly decreased invasive pneumococcal diseases worldwide in all age groups by herd protection effects [5, 6] . However, serotype replacement, i.e. replacement of vaccine serotypes by non-vaccine serotypes, has decreased the serotype coverage of PCVs over time [6, 7] . For Germany, we have described earlier the distribution of vaccine serotypes covered by the first but no longer available 7-valent conjugate vaccine and by the 13-valent conjugate vaccine (PCV13) between 2002 and 2016 in adult patients with CAP enrolled into the prospective multicentre study CAPNETZ [8, 9] is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 observational multi-centre cohort study of CAP-patients treated in the hospital or in the outpatients setting. CAPNETZ inclusion criteria were age 18 years, radiologically-confirmed pneumonia, and at least one of the following clinical findings: cough, purulent sputum, fever or focal chest sign on auscultation. Exclusion criteria were hospitalisation during 28 days preceding the study, immunosuppression and active tuberculosis [12] . All patients provided written informed consent prior enrolment to the study. Urine samples of enrolled patients were prospectively collected and immediately treated with 0.5M 1,4-Piperazinediethanesulfonic acid buffer (Boston BioProducts) to a final concentration of 25mM to stabilize respective polysaccharides. Two serotypespecific urine antigen detection (UAD) assays [13, 14] covering different serotypes on urine samples were performed and analysed at Pfizer's Vaccines Research and Development Laboratory (Pearl River, NY, USA). The UAD assay is a limit assay that uses Luminex technology, with positivity cut-off limits (based on antigen concentrations read off a standard curve), established for each serotype using 400 control urine specimens collected from otherwise healthy adults without CAP. Using nonparametric tolerance intervals, the assay . CC-BY 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.07.21264682 doi: medRxiv preprint 6 is set to achieve at least 97% specificity for each serotype. UAD1 covers PCV13 serotypes [13] and UAD2 covers 11 additional serotypes (the seven included in PCV20, i.e. ST8, ST10A, ST11A, ST12F, ST15B, ST22F, ST33F, and the four included in PPV23, i.e. ST2, ST9N, ST17F, ST20) [14] . UAD analyses were performed as described previously [13, 14] . Results were classified into "positive", "indeterminate" (excluded from analysis) and "negative". According to the recommendation of the German Standing Committee on Immunization (STIKO) for pneumococcal vaccination in adults, patients were classified as "at risk for pneumococcal disease" based on age 60 years or on the presence of at least one comorbidity regardless of age [15] . We quantified the distributions of pneumococcal vaccine serotypes of PCV13, PCV15, PCV20, and PPV23 as absolute and relative frequencies (relative to the number of patients with information on the respective serotype). Furthermore, we applied logistic mixed regression modelling to assess annual trends (dependent variable: each of PCV13, PCV15, PCV20, PPV23 and serotype 3; independent variable: year of CAP acquisition; random effect (intercept): study centre; reported results: odds ratio (OR) with 95% confidence interval (CI)). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint (2013-2014, 2015-2017 and 2018-2019) and the serotype proportion stratified by the above mentioned two STIKO classifications for patients "at risk" for pneumococcal disease (age 60 years or patients 18-59 years with ≥1 comorbidity). Serotype 3 was the most prevalent serotype in both patient subgroups, while the second most prevalent serotype was serotype 8 in patients 18-59 years with at-risk condition and serotype 11A in patients 60 years. . CC-BY 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.07.21264682 doi: medRxiv preprint 8 In conclusion, PCV20 had a substantially higher coverage of all-cause CAP in adults compared to PCV13 (11.7% versus 7.3%) for age group 18-59 years with ≥1 comorbidity and 12.6% versus 7.7% for age group 60 years. Our data show, that i) the infant vaccination program of PCV13, which started in Germany 2010 did not result in a relevant and sustained decrease of PCV13 serotypes in pneumonia in adults and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time. The presented data may be of use for modelling impact of pneumococcal vaccines and may contribute to informed decision making of vaccination committees. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 All authors have made substantial contribution to the study design, data collection, analysis or interpretation, drafting the article and revising it critically for important intellectual content. All authors approved the final version to be is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 7, 2021 Pink (Department of Pneumology Institute of Infectious Diseases and Infection Control (IIMK) Clinic for Internal Medicine I, Department of Cardiology Medical Clinic-Pneumology, Brüderkrankenhaus St Baldesberger (Department of Infectiology and Hospital Hygiene Institute for Medical Microbiology and References 1. Brooks LRK, Mias GI. Streptococcus pneumoniae's Virulence and Host Immunity: Aging, Diagnostics, and Prevention The burden of pneumococcal pneumonia -experience of the German competence network CAPNETZ The Alere BinaxNOW Pneumococcal Urinary Antigen Test: Diagnostic Sensitivity for Adult Pneumococcal Pneumonia and Relationship to Specific Serotypes Pneumococcal Community-Acquired Pneumonia Detected by Serotype-Specific Urinary Antigen Detection Assays Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15 Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study Invasive pneumococcal disease incidence in children and adults in France during the pneumococcal author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted Qualification and Clinical Validation of an Immunodiagnostic Assay for detecting 11 additional Streptococcus pneumoniae Serotype-specific Polysaccharides in Human Urine German Standing Committee on Vaccination at the Robert Koch Institute. Recommendation of the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute -2016/2017 valent pneumococcal conjugate vaccine; PCV15 -15-valent pneumococcal conjugate vaccine; PCV20 -20-valent pneumococcal conjugate vaccine; PPV23 -23-valent pneumococcal polysaccharide vaccine, ST -serotype, STIKO -German Standing Committee on Immunization It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted October 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021