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Diagnostic Laboratory Immunology

Validation of an Immunodiagnostic Assay for Detection of 13 Streptococcus pneumoniae Serotype-Specific Polysaccharides in Human Urine

Michael W. Pride, Susanne M. Huijts, Kangjian Wu, Victor Souza, Sherry Passador, Chunyan Tinder, Esther Song, Arik Elfassy, Lisa McNeil, Ronald Menton, Roger French, Janice Callahan, Chris Webber, William C. Gruber, Marc J. M. Bonten, Kathrin U. Jansen
Michael W. Pride
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Susanne M. Huijts
bJulius Center for Public Health and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
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Kangjian Wu
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Victor Souza
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Sherry Passador
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Chunyan Tinder
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Esther Song
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Arik Elfassy
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Lisa McNeil
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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Ronald Menton
cBiotechnology Unit and Oncology Clinical Research Statistics, Pfizer Research, Cambridge, Massachusetts, USA, and Pearl River, New York, USA
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Roger French
cBiotechnology Unit and Oncology Clinical Research Statistics, Pfizer Research, Cambridge, Massachusetts, USA, and Pearl River, New York, USA
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Janice Callahan
dCallahan Associates Inc., La Jolla, California, USA
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Chris Webber
eVaccine Clinical Research, Pfizer Research, Maidenhead, United Kingdom
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William C. Gruber
fVaccine Clinical Research, Pfizer Research, Pearl River, New York, USA
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Marc J. M. Bonten
bJulius Center for Public Health and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
gDepartment of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
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Kathrin U. Jansen
aVaccine Research East and Early Development, Pfizer Research, Pearl River, New York, New York, USA
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DOI: 10.1128/CVI.00064-12
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Article Figures & Data

Tables

  • Additional Files
  • Table 1

    Specificity of UAD assay's 13 serotype-specific monoclonal antibodies to 91 strains of S. pneumoniae bacteria

    S. pneumoniae serotypeMFI for MAb specific for the following S. pneumoniae serotype:
    Control mouse IgG13456A6B7F9V1418C19A19F23F
    112316,569a334339315335315264343328350380426366
    3554617,6475840485665475452525146
    434426026952,681255269265285305297281265467263
    51227868698,1867764686466706512970
    6A1845364617310,8686249706959577255
    6B127927911375-3720,2559067949461172100
    7F150911131541441046111,98695571307513982
    9V157122801061410311511416,617164768810767
    142021591561861682011911871366,308205161213123
    18C1841331731771811441451701901737,387121213129
    19A1981076666315815649596113418,7786058
    19F125574639424645525670444816,54545
    23F18221819622522818515819917511419520520412,842
    6C73403125434,770383132355034731
    7A13957324740474845,1875546474710940
    9A68504951464653559735751497546
    18A32110090891289810614912211816,03185112115
    18B3777324647524253465816,930517133
    18Fb69482632684736384038436,344406741
    • ↵a Values in bold indicate positive MFI reactivity (>4 times control mouse IgG MFI).

    • ↵b For all other S. pneumoniae strains (n = 72), values were ≤4 times the MFI of the control mouse IgG MFI.

  • Table 2

    Specificity of S. pneumoniae UAD assay

    S. pneumoniae serotypeSignal produced by MAb-coated microspheres
    13456A6B7F9V1418C19A19F23F
    MFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/NMFIS/N
    121,067a74424191491221391291561291181301401591
    332122,335967101461241371291471331191301421761
    430125111,6291,264461251481271491331181321441791
    541126111115,841362352381311451301191301441791
    6A31127111152122,8171,061371301491331191331421821
    6B32128111147139223,0407052915613312113014211051
    7F32126111146125138121,1078004713111912914111121
    9V27125111144122135125119,962476301211281371911
    1429125110146124135127142123,065759181301511951
    18C30126110146122133128144129116,354962281391991
    19A28126110148124134126140129119123,555850431831
    19F2612519143123132126144130118130122,579591961
    23F32122110143124133128142129117129138124,240316
    2b361916142140172123146130181301871111
    8b3611516142137180127147131161341861121
    9Nb3711215142141176129147133171331891101
    10Ab3611116140139172127144130171311821101
    11Ab3611116143139179127150133181381931111
    12Fb3911216155139178127147132181331901131
    15Bb451131714114516612716313511213212043161
    17Fb41112171371431591211611271101241711171
    20b36111161411371701241220598381311871161
    22Fb3311015147157271122144128181301791121
    33Fb3711117142139175125147131171331801121
    • ↵a Values in bold indicate serotype-specific reactivity.

    • ↵b Additional 23v serotypes.

  • Table 3

    Accuracy of UAD assay

    SerotypePositivity cutoff value (PnPS U/ml)Assay range based on accuracy
    Lower limitUpper limit
    GMCRSD (%)GMCRSD (%)
    117.81.18.81,034.12.3
    3330.51.08.8997.22.8
    427.30.77.1917.011.8
    52.51.210.3746.85.5
    6A106.71.110.01,033.23.8
    6B79.71.311.1796.65.5
    7F6.61.24.5502.07.3
    9V15.68.48.82,984.89.1
    141.70.511.6344.94.8
    18C4.30.69.5724.05.5
    19A9.82.321.2760.16.0
    19F150.01.27.5504.81.6
    23F8.01.46.6906.33.5
  • Table 4

    Precision and sample linearity of UAD assay

    SerotypePositivity cutoff value (PnPS U/ml)Assay range based on:
    PrecisionSample linearity
    GMC (PnPS U/ml)% RSD rangeGMC (PnPS U/ml)% biasa range
    Lower limitUpper limitLower limitUpper limit
    117.89.1477.25.5–25.59.1477.282.6–117.5
    3330.58.61,153.35.7–24.18.61,153.371.4–114.0
    427.31.9192.56.5–13.21.9192.594.6–110.6
    52.50.832.98.5–15.21.132.982.2–119.8
    6A106.74.8644.72.9–12.34.8472.177.1–123.8
    6B79.74.3504.25.7–21.34.3504.289.6–114.8
    7F6.60.5211.35.1–14.50.6165.480.4–121.1
    9V15.64.31,480.510.3–27.85.91,480.572.5–122.5
    141.70.616.45.7–15.10.616.490.2–110.6
    18C4.30.615.211.0–15.10.615.288.8–116.2
    19A9.89.8174.310.6–26.72.0174.368.1*–115.3
    19F150.05.3428.65.4–6.45.3428.685.3–111.5
    23F8.02.9122.48.1–14.52.985.672.9–119.0
    • ↵a Sample linearity is considered acceptable if the percent relative bias for any one dilution is outside of the acceptance criterion but the percent relative bias for the dilutions immediately above and below this dilution is within the acceptance criterion.

  • Table 5

    Final UAD assay range

    SerotypePositivity cutoff value (PnPS U/ml)Final assay GMC range (PnPS U/ml)
    Lower limitUpper limit
    117.89.1477.2
    3330.58.6997.2
    427.31.9192.5
    52.51.232.9
    6A106.74.8472.1
    6B79.74.3504.2
    7F6.61.2165.4
    9V15.68.41,480.5
    141.70.616.4
    18C4.30.615.2
    19A9.89.8174.3
    19F150.05.3428.6
    23F8.02.985.6
  • Table 6

    Clinical validation of UAD assay

    Blood culture-confirmed serotypeNo. of urine samplesUAD assayUAD clinical sensitivity compared to blood culture (%)No. of samples positive by BinaxNOW S. pneumoniae urine antigen test
    No. of positive samplesNo. of negative samplesClinical specificity (%)
    Prevnar13 S. pneumoniae serotypes
        17701001003
        310110000
        43301001002
        51101001001
        6A/C1101001000
        6B000NAaNA0
        7F/A4401001003
        9V/A2201001002
        147701001005
        18000NANA0
        19A6601001005
        19F000NANA0
        23F2201001002
            Total3433110097.123
    Non-Prevnar13 S. pneumoniae serotypes
        83031003
        8A1011000
        9N2021001
        10A1011001
        11A1011000
        16F3031002
        201011000
        22F5051001
            Total170171008
    • ↵a NA, not applicable.

  • Table 7

    Comparison of results from UAD assay and BinaxNOW assay in bacteremic and nonbacteremic CAP

    CAP casesNo. of casesUAD assayBinaxNOW S. pneumoniae urine antigen test
    No. of positive samplesNo. of negative samplesSensitivity compared to blood culture (%)No. of positive samplesdSensitivity compared to blood culture (%)
    Total blood culture positive (bacteremic CAP)69343534
        S. pneumoniae positive
        Prevnar 13 serotypes34331972367.6
        Non-Prevnar 13 serotypes17017NAe847.1
        Nonserotypeable312NA2NA
        Non-S. pneumoniae15015NA1NA
    Total blood culture negative (nonbacteremic CAP)707141566NA126cNA
    Indeterminate1/707NANANA1/707NA
    Total CAP (bacteremic and nonbacteremic)776175a601NA160bNA
    • a 22.6% (175/776) of total CAP samples were UAD assay positive.

    • ↵b 20.6% (160/776) of total CAP samples were BinaxNOW assay positive.

    • ↵c Seventy-one of the 126 BinaxNOW-positive samples (nonbacteremic CAP) were also UAD assay positive.

    • ↵d 12.1% (23 + 71/776) of all BinaxNOW-positive samples were also UAD positive (Prevnar 13 serotypes).

    • e NA, not applicable.

Additional Files

  • Tables
  • Supplemental material

    Files in this Data Supplement:

    • Supplemental file 1 -

      Table S1. Specificity of the UAD assay’s 13 serotype-specific monoclonal antibodies to 407 non-S. pneumoniae organisms. Table S2. Clinical validation of the UAD assay blood culture-confirmed non-S. pneumoniae organisms.

      PDF, 16K

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Validation of an Immunodiagnostic Assay for Detection of 13 Streptococcus pneumoniae Serotype-Specific Polysaccharides in Human Urine
Michael W. Pride, Susanne M. Huijts, Kangjian Wu, Victor Souza, Sherry Passador, Chunyan Tinder, Esther Song, Arik Elfassy, Lisa McNeil, Ronald Menton, Roger French, Janice Callahan, Chris Webber, William C. Gruber, Marc J. M. Bonten, Kathrin U. Jansen
Clinical and Vaccine Immunology Jul 2012, 19 (8) 1131-1141; DOI: 10.1128/CVI.00064-12

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Validation of an Immunodiagnostic Assay for Detection of 13 Streptococcus pneumoniae Serotype-Specific Polysaccharides in Human Urine
Michael W. Pride, Susanne M. Huijts, Kangjian Wu, Victor Souza, Sherry Passador, Chunyan Tinder, Esther Song, Arik Elfassy, Lisa McNeil, Ronald Menton, Roger French, Janice Callahan, Chris Webber, William C. Gruber, Marc J. M. Bonten, Kathrin U. Jansen
Clinical and Vaccine Immunology Jul 2012, 19 (8) 1131-1141; DOI: 10.1128/CVI.00064-12
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    • ABSTRACT
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