Qualification and Clinical Validation of an Immunodiagnostic Assay for Detecting 11 Additional Streptococcus pneumoniae Serotype–specific Polysaccharides in Human Urine

Abstract

Background Identifying Streptococcus pneumoniae serotypes by urinary antigen detection (UAD) assay is the most sensitive way to evaluate the epidemiology of nonbacteremic community-acquired pneumonia (CAP). We first described a UAD assay to detect the S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, covered by the licensed 13-valent S. pneumoniae conjugate vaccine. To assess the substantial remaining pneumococcal disease burden after introduction of several pneumococcal vaccines, a UAD-2 assay was developed to detect 11 additional serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F) in individuals with radiographically confirmed CAP. Methods The specificity of the UAD-2 assay was achieved by capturing pneumococcal polysaccharides with serotype-specific monoclonal antibodies, using Luminex technology. Assay qualification was used to assess accuracy, precision, and sample linearity. Serotype positivity was based on cutoffs determined by nonparametric statistical evaluation of urine samples from individuals without pneumococcal disease. The sensitivity and specificity of the positivity cutoffs were assessed in a clinical validation, using urine samples obtained from a large study that measured the proportion of radiographically confirmed CAP caused by S. pneumoniae serotypes in hospitalized US adults. Results The UAD-2 assay was shown to be specific and reproducible. Clinical validation demonstrated assay sensitivity and specificity of 92.2% and 95.9% against a reference standard of bacteremic pneumonia. In addition, the UAD-2 assay identified a S. pneumoniae serotype in 3.72% of nonbacteremic CAP cases obtained from hospitalized US adults. When combined with bacteremic CAP cases, the proportion of pneumonias with a UAD-2 serotype was 4.33%. Conclusions The qualified/clinically validated UAD-2 method has applicability in understanding the epidemiology of nonbacteremic S. pneumoniae CAP and for assessing the efficacy of future pneumococcal conjugate vaccines that are under development.

The Evolution and Distribution of Pneumococcal Serotypes in Adults Hospitalized With Community-Acquired Pneumonia in Spain Using a Serotype-Specific Urinary Antigen Detection Test: The CAPA Study, 2011–2018

“…Additionally, UAD1/2 assays are highly sensitive and specific for bacteremic pneumonia compared with the gold standard of blood culture. However, UAD1/2 sensitivity for nonbacteremic pneumonia is unknown because no reference standard exists [ 37 ]. Consequently, we may have underestimated the contribution of UAD1/2 serotypes to nonbacteremic pneumonia in our study.…”

Pneumokokkenimpfstoffe

“…PCV20 wurde am 09.06.2021 durch die FDA zunächst für Erwachsene zugelassen. Eine Untersuchung mit dem bekannten SSUAD [ 23 ] und einem neu etablierten SSUAD [ 30 ] an 1130 erwachsenen Patienten mit „all cause“ CAP, die nach Einführung der PCV13-Impfung bei Kindern in Deutschland eingeschlossen wurden (2013–2018), zeigt, dass 8,3 % aller Fälle durch PCV13-Serotypen, 13,0 % durch PCV20-Serotypen und 13,9 % durch PPV23-Serotypen hervorgerufen wurden [ 31 ]. Der Unterschied in der Serotypenerfassung zwischen PPV23 und PCV20 ist also relativ gering.…”

A randomized phase 1/2 study of the safety and immunogenicity of a multivalent pneumococcal conjugate vaccine in healthy adults 50 through 85 years of age

“…[16][17][18][19]34 This 2-stage phase 1/2 study assessed the safety and immunogenicity of cPCV7, a novel PCV that targets 7 pneumococcal serotypes not included in PCV13; these serotypes were selected based on relative prevalence as a cause of IPD and nonbacteremic pneumonia, geographic distribution, antibiotic resistance, and disease severity characteristics. 17,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] In this first-in-human study, cPCV7 was well tolerated and elicited functional immune responses in healthy adults 50 to 85 years of age. The two study stages allowed for an efficient transition to move from a phase 1 type evaluation that focused primarily on describing initial safety and immunogenicity to a phase 2 evaluation with a larger and older population with a licensed pneumococcal vaccine as a control to further assess safety and immunogenicity.…”

“…These seven serotypes were selected based on prevalence, geographic distribution, and association with antibiotic resistance and greater disease severity. 17,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] Of note, in Germany in 2017 and 2018, these 7 additional serotypes accounted for approximately 30% of all cases of IPD in adults 60 years of age and older. 33 Moreover, in US adults of any age, it has been estimated that these serotypes account for approximately 9990 cases of IPD and 44,000 cases of inpatient pneumonia annually.…”