Abstract
In Germany, the recently approved 20-valent pneumococcal conjugate vaccine had a substantially higher coverage against pneumonia in adults than the 13-valent vaccine, while the coverage gap compared to the 23-valent polysaccharide vaccine was small https://bit.ly/3q4skov
To the Editor:
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 often remain negative in hospitalised 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-bacteraemic 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 pneumococcal conjugate vaccine (PCV7) and the 13-valent conjugate vaccine (PCV13) between 2002 and 2016 in adult patients with CAP enrolled into the prospective multicentre study CAPNETZ [8, 9]. PCV7 was replaced by either the 10-valent conjugate vaccine or, mainly, PCV13 in the German infant vaccination programme in 2010. However, PCV10 held the smallest market share of only 8% of pneumococcal vaccines in Germany in 2018 [10]. In adults, the German Standing Committee on Immunization (STIKO) recommends the 23-valent pneumococcal polysaccharide vaccine (PPV23) as routine pneumococcal vaccination for all adults of 60 years and above and for all patients with defined chronic comorbidities predisposing to pneumococcal disease, regardless of age. Moreover, since 2016, sequential vaccination with PCV13 followed by PPV23 is recommended for German adults at high risk for pneumococcal disease, including individuals with immunosuppression, chronic liver disease, chronic kidney disease and individuals with cerebrospinal fluid leaks or cochlear implants [11]. Recently, a 15-valent (PCV15) and a 20-valent conjugate vaccine (PCV20) have been licensed for the adult indication by the US Food and Drug Administration and are under evaluation by the European Medicines Agency [12, 13]. PCV15 contains all serotypes of PCV13 plus serotype 22F and 33F and PCV 20 includes PCV13 serotypes plus serotypes 8, 10A, 11A, 12F, 15B, 22F and 33F.
The aim of the present study was to evaluate serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20 and PPV23 among adult patients with all-cause CAP between 2013 and 2019. All patients enrolled in the CAPNETZ study in Germany between 1 January, 2013 and 31 December, 2019 with an available urine sample were included in the analysis. The CAPNETZ study (German Clinical Trials Register: DRKS00005274; approval number of leading ethics committee Medical Faculty of Otto-von-Guericke-University Magdeburg: 104/01; see acknowledgment or www.capnetz.de for participating centres) is a prospective observational multicentre cohort study of CAP patients treated in the hospital or in the outpatient 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 the 28 days preceding the study, immunosuppression and active tuberculosis [14]. All patients provided written informed consent prior to enrolment to the study. Urine samples of enrolled patients were prospectively collected and immediately treated with 0.5 M 1,4-piperazinediethanesulfonic acid buffer (Boston BioProducts) to a final concentration of 25 mM to stabilise respective polysaccharides. Two serotype-specific urine antigen detection (UAD) assays [15, 16] 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 is set to achieve at least 97% specificity for each serotype. UAD1 covers PCV13 serotypes [14] and UAD2 covers 11 additional serotypes (the seven included in PCV20, i.e. ST8, ST10A, ST11A, ST12F, ST15B, ST22F and ST33F, and the four included in PPV23, i.e. ST2, ST9N, ST17F and ST20) [16]. UAD analyses were performed as described previously [15, 16]. Results were classified into “positive”, “indeterminate” (excluded from analysis) and “negative”. According to the STIKO recommendation 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 [11]. We quantified the distribution 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 with 95% confidence interval).
Out of 1831 patients screened, urine samples with a valid UAD test result were available for 1343 patients (73.3%) who were enrolled by 26 CAPNETZ centres distributed widely over Germany. Among these 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 1204 patients (89.7%) were treated in the hospital. Among the 1108 patients at risk for pneumococcal disease, only 179 patients (16.2%) reported any pneumococcal vaccination within the previous 5 years. In the overall study population during the study period 2013 to 2019, 183 of 1343 (13.6%) patients had a positive UAD1/2 test result. The most common vaccine serotypes were serotype 3 (n=49; 3.7% of all-cause CAP), followed by serotype 8 (n=21; 1.6% of all-cause CAP), serotype 22F (n=13; 1.0% of all-cause CAP) and serotype 11A (n=11; 0.8% of all-cause CAP). As shown in table 1, the overall proportion of vaccine-type pneumonia among all-cause pneumonia for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178), respectively. When regarding only pneumococcal pneumonia diagnosed by conventional diagnostics (PUAT or blood culture; n=74), PCV13, PCV15, PCV20 and PPV23 coverage was 37.8% (n=28), 44.6% (n=33), 64.9% (n=48) and 66.2% (n=49), respectively. Bacteraemic pneumococcal CAP was detected in 19 (2.1%) of the 889 patients for whom blood cultures were obtained. Among them, bacteraemic pneumococcal CAP was caused by serotype 8 in four patients (21.1%), serotype 4 and serotype 7F in two patients (10.5%), and serotype 3, serotype 12F, serotype 14, serotype 20 and serotype 33F in one patient (5.3%) each. The coverage of PCV13, PCV15, PCV20 and PPV23 in patients with bacteraemic CAP was 31.6% (n=6), 36.8% (n=7), 63.2% (n=12), and 68.4% (n=13). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage (serotype 3: OR 0.95, 95% CI 0.81–1.10; 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). Table 1 provides the serotype proportions of all-cause CAP for three time periods (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.
Distribution of pneumococcal serotypes aggregated by pneumococcal vaccine formulation in patients with radiologically confirmed community-acquired pneumonia by UAD1/UAD2 by study period and in patient subgroups with STIKO recommendation for pneumococcal vaccination (individuals ≥60 years and individuals 18–59 years with at-risk condition, i.e. ≥1 comorbidity)
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: 1) no decline of PCV13 serotypes in all-cause CAP between 2013–2019 mainly due to a persistently high proportion of serotype 3, suggesting no meaningful effect of childhood PCV13 vaccination on PCV13 coverage in pneumonia in adults during this time period; and 2) 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.
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Acknowledgements
CAPNETZ is a multidisciplinary approach to better understand and treat patients with community-acquired pneumonia. Members of the CAPNETZ study group are: W. Knüppel (Dept of Internal Medicine, Bad Arolsen Hospital); D. Stolz (Dept of Pneumology, University Hospital Basel, Switzerland); W. Bauer (Central Emergency Admission/Medical Admission Ward, Charité-Universitätsmedizin Berlin); N. Suttorp, A. Mikolajewska and M. Witzenrath (Medical Dept, Division of Infectiology and Pneumonology Charité-Universitätsmedizin Berlin); S. Gläser and D. Thiemig (Dept of Internal Medicine – Pneumology and Infectiology, Vivantes Hospital Neukölln, Berlin-Neukölln); C. Boesecke (Medical Clinic and Policlinic I – General Internal Medicine, University Hospital Bonn); M. Prediger (III. Medical Clinic, Carl-Thiem Hospital Cottbus); B. Schaaf, J. Kremling and D. Nickoleit-Bitzenberger (Pneumology, Infectiology and Internal Intensive Care Medicine, Medical Clinic Nord, Dortmund); M. Kolditz, B. Schulte-Hubbert and S. Langner (Medical Clinic I Dept of Pneumology, University Hospital Dresden); C. Stephan (Medical Clinic II/Infectiology, University Hospital Frankfurt); G. Rohde and C. Bellinghausen (Medical Clinic I – Pneumology/Allergology, University Hospital Frankfurt); M. Panning (Institute of Virology, University Hospital Freiburg); C. Neurohr (Dept of Pneumology and Respiratory Medicine, Clinic Schillerhöhe, Gerlingen); T. Welte and I. Pink (Dept of Pneumology, Hannover Medical School, Hanover); G. Barten-Neiner, W. Kröner, M. Nawrocki and J. Naim, (CAPNETZ Office, Hannover); T. Illig and N. Klopp (Hannover Unified Biobank, Hannover Medical School); M. Pletz, B. Schleenvoigt and C. Bahrs (Institute of Infectious Diseases and Infection Control (IIMK), University Hospital Jena); C. Kroegel and A. Moeser (Clinic for Internal Medicine I, Dept of Cardiology, Angiology, Pneumology, Internistic Intensive Medicine, University Hospital Jena); D. Drömann, P. Parschke and K. Franzen (Medical Clinic III, Pneumology/Infectiology, University Medical Center Schleswig-Holstein, Lübeck); J. Rupp and N. Käding (Dept of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein, Lübeck); G. Wesseling, K. Walraven and D. Braeken (Dept of Respiratory Medicine, Maastricht University Medical Center, The Netherlands); C. Spinner (Dept of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, School of Medicine); A. Zaruchas (Medical Clinic-Pneumology, Brüderkrankenhaus St. Josef, Paderborn); M. Falcone and G. Tiseo (Dept of Clinical and Experimental Medicine, Universita die Pisa, Italy); D. Heigener and I. Hering (Dept of Pneumology, Agaplesion Diakonieklinikum Rotenburg); W. Albrich, F. Waldeck, F. Rassouli and S. Baldesberger (Dept of Infectiology and Hospital Hygiene, Kantonsspital St. Gallen, Switzerland); S. Stenger (Institute for Medical Microbiology and Hygiene, University Hospital Ulm); M. Wallner (2mt Software, Ulm); H. Burgmann, L. Traby and L. Schubert (Dept of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna); and all study nurses.
Footnotes
Author contributions: 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 submitted. M. Kolditz, S. Ewig, G. Rohde, G. Barten-Neiner, J. Rupp, M. Witzenrath, T. Welte and M.W. Pletz designed the study; C. Bahrs, M. Kesselmeier and M.W. Pletz drafted the article; C. Bahrs and M. Kesselmeier performed the statistical analysis; C. Bahrs, M. Kolditz, M. Kesselmeier, S. Ewig, G. Rohde, G. Barten-Neiner, J. Rupp, M. Witzenrath, T. Welte and M.W. Pletz contributed to the critical revisions, and final approval of the article.
Conflict of interest: C. Bahrs is a member of the scientific advisory board of GSK, reports personal fees from Pfizer for lectures, and has received support for attending meetings and travel, all outside the submitted work.
Conflict of interest: M. Kesselmeier declares no conflict of interest.
Conflict of interests: M. Kolditz reports personal fees from Berlin Chemie, Boehringer, AstraZeneca, Biotest, Novartis, GSK, Gilead, Pfizer and MSD, and a research grant from Pfizer, outside the submitted work.
Conflict of interest: S. Ewig is member of the scientific advisory board of Pfizer.
Conflict of interest: G. Rohde reports personal fees from AstraZeneca, Berlin Chemie, BMS, Pfizer, Boehringer Ingelheim, Solvay, Insmed, GSK, Essex Pharma, MSD, Grifols, Chiesi, Vertex, Roche, Takeda and Novartis for lectures including service on speakers’ bureaus and/or consultancy during advisory board meetings, and personal fees from GSK for travel accommodations/meeting expenses, outside the submitted work.
Conflict of interest: As part of her activity as a member of the executive bodies, G. Barten-Neiner reports economic connections to the following diagnostic and pharmaceutical companies: ThermoFisher Scientific/BRAHMS, Alere Technologies GmbH, Merck Sharp & Dohme Corp., Pfizer Pharma GmbH, R-Biopharm AG and Helmut Hund GmbH.
Conflict of interest: J. Rupp has nothing to disclose.
Conflict of interest: M. Witzenrath received personal fees from AstraZeneca, Bayer Health Care, Berlin Chemie, Biotest, Chiesi, Novartis and Teva, and research funding from Actelion, Bayer Health Care, Biotest and Boehringer Ingelheim, all unrelated to the current work.
Conflict of interest: T. Welte is the head of clinical studies and a member of the speakers’ bureau for Pfizer, Bio Merieux and Roche Diagnostics, and is a consultant to Pfizer and MSD.
Conflict of interest: M.W. Pletz is a consultant to and a member of the speakers’ bureau for Bayer, MSD, Pfizer, meduptodate, Thermofisher and Novartis, and has received research grants from Pfizer.
Support statement: CAPNETZ was founded by a German Federal Ministry of Education and Research grant (01KI07145) 2001–2011. Since 2013, CAPNETZ has been supported by the German Center for Lung Research (DZL): 2013–2015 funding code 82DZL00204 and 2016–2020 funding code 82DZL002A4. C. Bahrs and M.W. Pletz are partly supported by a grant of the Federal Ministry of Education and Research KliFo 2.0 (grant number 01KI1501). M. Witzenrath is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9, SFB 1449 B2, by the German Ministry of Education and Research (BMBF) in the framework of the CAPSyS (01ZX1304B), CAPSyS-COVID (01ZX1604B), SYMPATH (01ZX1906A), PROVID (01KI20160A) P4C (16GW0141), MAPVAP (16GW0247), NUM-NAPKON (01KX2021), and by the Berlin Institute of Health (CM-COVID). This study was supported by an unrestricted grant from Pfizer. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 7, 2021.
- Accepted November 1, 2021.
- Copyright ©The authors 2022.
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