Humoral immune disorders, such as common variable immunodeficiency (CVID) and specific antibody deficiency (SAD), require functional testing for proper assessment and management. The most common testing involves the measurement of pre- and post-vaccination pneumococcal titers to assess polysaccharide antibody response to the 23-valent pneumococcal vaccine (PPSV23). Guidelines for this testing remain controversial and have become increasingly challenging with the widespread use of pneumococcal conjugate vaccines (PCV) such as PCV20, which have decreased the number of unique serotypes contained in PPSV23 that are available for assessing anti-polysaccharide antibody responses.
To determine the diagnostic utility in evaluating the polysaccharide antibody response to the four or eleven pneumococcal serotypes unique to PPSV23 in patients previously vaccinated with PCV20 or PCV13, respectively.
We performed a retrospective chart review using electronic medical records of patients aged 2-65 years old seen in University of Virginia Health Immunodeficiency Clinics who received PPSV23 and had pneumococcal titers measured within 8 weeks of vaccination (see table). Pneumococcal titers were measured using a 23-serotype bead-based multiplex immunoassay panel via Mayo Clinic Laboratories. A protective response was defined as ≥1.3 µg/mL, and a response to PPSV23 was classified as “positive” based on responding to ≥70% of the unique serotypes not contained in previously received PCV for each subject.
Pneumococcal Vaccine Serotypes
| Serotypes | PCV-7a | PCV-13b | PCV-15c | PCV-20d | PCV-21e | PPSV23 |
|---|---|---|---|---|---|---|
| 1 | – | 1 | 1 | 1 | – | 1 |
| 2 | – | – | – | – | – | 2 |
| 3 | – | 3 | 3 | 3 | 3 | 3 |
| 4 | 4 | 4 | 4 | 4 | – | 4 |
| 5 | – | 5 | 5 | 5 | – | 5 |
| 6A | – | 6A | 6A | 6A | 6A | – |
| 6B | 6B | 6B | 6B | 6B | – | 6B |
| 7F | – | 7F | 7F | 7F | 7F | 7F |
| 8 | – | – | – | 8 | 8 | 8 |
| 9N | – | – | – | – | 9N | 9N |
| 9V | 9V | 9V | 9V | 9V | – | 9V |
| 10A | – | – | – | 10A | 10A | 10A |
| 11A | – | – | – | 11A | 11A | 11A |
| 12F | – | – | – | 12F | 12F | 12F |
| 14 | 14 | 14 | 14 | 14 | – | 14 |
| 15A | – | – | – | – | 15A | – |
| 15B | – | – | – | 15B | – | 15B |
| 15C | – | – | – | – | 15C | – |
| 16F | – | – | – | – | 16F | – |
| 17F | – | – | – | – | 17F | 17F |
| 18C | 18C | 18C | 18C | 18C | – | 18C |
| 19A | – | 19A | 19A | 19A | 19A | 19A |
| 19F | 19F | 19F | 19F | 19F | – | 19F |
| 20 | – | – | – | – | 20 | 20 |
| 22F | – | – | 22F | 22F | 22F | 22F |
| 23A | – | – | – | – | 23A | – |
| 23B | – | – | – | – | 23B | – |
| 23F | 23F | 23F | 23F | 23F | – | 23F |
| 24F | – | – | – | – | 24F | – |
| 31 | – | – | – | – | 31 | – |
| 33F | – | – | 33F | 33F | 33F | 33F |
| 35B | – | – | – | – | 35B | – |
| Serotypes | PCV-7a | PCV-13b | PCV-15c | PCV-20d | PCV-21e | PPSV23 |
|---|---|---|---|---|---|---|
| 1 | – | 1 | 1 | 1 | – | 1 |
| 2 | – | – | – | – | – | 2 |
| 3 | – | 3 | 3 | 3 | 3 | 3 |
| 4 | 4 | 4 | 4 | 4 | – | 4 |
| 5 | – | 5 | 5 | 5 | – | 5 |
| 6A | – | 6A | 6A | 6A | 6A | – |
| 6B | 6B | 6B | 6B | 6B | – | 6B |
| 7F | – | 7F | 7F | 7F | 7F | 7F |
| 8 | – | – | – | 8 | 8 | 8 |
| 9N | – | – | – | – | 9N | 9N |
| 9V | 9V | 9V | 9V | 9V | – | 9V |
| 10A | – | – | – | 10A | 10A | 10A |
| 11A | – | – | – | 11A | 11A | 11A |
| 12F | – | – | – | 12F | 12F | 12F |
| 14 | 14 | 14 | 14 | 14 | – | 14 |
| 15A | – | – | – | – | 15A | – |
| 15B | – | – | – | 15B | – | 15B |
| 15C | – | – | – | – | 15C | – |
| 16F | – | – | – | – | 16F | – |
| 17F | – | – | – | – | 17F | 17F |
| 18C | 18C | 18C | 18C | 18C | – | 18C |
| 19A | – | 19A | 19A | 19A | 19A | 19A |
| 19F | 19F | 19F | 19F | 19F | – | 19F |
| 20 | – | – | – | – | 20 | 20 |
| 22F | – | – | 22F | 22F | 22F | 22F |
| 23A | – | – | – | – | 23A | – |
| 23B | – | – | – | – | 23B | – |
| 23F | 23F | 23F | 23F | 23F | – | 23F |
| 24F | – | – | – | – | 24F | – |
| 31 | – | – | – | – | 31 | – |
| 33F | – | – | 33F | 33F | 33F | 33F |
| 35B | – | – | – | – | 35B | – |
16 serotypes contained in PPSV23 that are not contained in PCV7: 1, 2, 3, 5, 7F, 8, 9N, 10A, 11A, 12F, 15B, 17F, 19A, 20, 22F, 33F
11 serotypes contained in PPSV23 that are not contained in PCV13: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F
9 serotypes contained in PPSV23 that are not contained in PCV15: 8, 10A, 11A, 12F, 15B, 2, 9N, 17F, 20
4 serotypes contained in PPSV23 that are not contained in PCV20: 2, 9N, 17F, 20
11 serotypes contained in PPSV23 that are not contained in PCV21: 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F, 15B, 2
Diagnostic agreement summary between the pneumococcal antibody 4 and 11 serotype panel findings and the pneumococcal antibody 23 serotype panel findings when the pneumococcal antibody 23 serotype panel finding is considered the gold standard.
| 23 Serotype Response | ||
|---|---|---|
| 11 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 23 | 0 |
| Non-responder (<70% Positive) | 4 | 12 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 96.7 [82.8, 99.9] | |
| Specificity | 66.7 [48.2, 82.0] | |
| PPV | 72.5 [56.1, 85.4] | |
| NPV | 95.7 [78.0, 99.9] | |
| FPER | 33.3 [18.0, 51.8] | |
| FNER | 3.3 [ 0.1, 17.2] | |
| Accuracy | 81.0 [69.1, 89.8] | |
| 23 Serotype Response | ||
|---|---|---|
| 11 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 23 | 0 |
| Non-responder (<70% Positive) | 4 | 12 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 96.7 [82.8, 99.9] | |
| Specificity | 66.7 [48.2, 82.0] | |
| PPV | 72.5 [56.1, 85.4] | |
| NPV | 95.7 [78.0, 99.9] | |
| FPER | 33.3 [18.0, 51.8] | |
| FNER | 3.3 [ 0.1, 17.2] | |
| Accuracy | 81.0 [69.1, 89.8] | |
| 23 Serotype Response | ||
|---|---|---|
| 4 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 22 | 2 |
| Non-responder (<70% Positive) | 5 | 10 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 81.5 [61.9, 93.7] | |
| Specificity | 83.3 [51.6, 97.9] | |
| PPV | 91.7 [73.0, 99.0] | |
| NPV | 66.7 [38.4, 88.2] | |
| FPER | 16.7 [ 2.1, 48.4] | |
| FNER | 18.5 [ 6.3, 38.1] | |
| Accuracy | 82.1 [66.5, 92.5] | |
| 23 Serotype Response | ||
|---|---|---|
| 4 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 22 | 2 |
| Non-responder (<70% Positive) | 5 | 10 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 81.5 [61.9, 93.7] | |
| Specificity | 83.3 [51.6, 97.9] | |
| PPV | 91.7 [73.0, 99.0] | |
| NPV | 66.7 [38.4, 88.2] | |
| FPER | 16.7 [ 2.1, 48.4] | |
| FNER | 18.5 [ 6.3, 38.1] | |
| Accuracy | 82.1 [66.5, 92.5] | |
| 11 Serotype Response | ||
|---|---|---|
| 4 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 33 | 7 |
| Non-responder (<70% Positive) | 3 | 20 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 91.7 [77.5, 98.2] | |
| Specificity | 74.1 [53.7, 88.9] | |
| PPV | 82.5 [67.2, 92.7] | |
| NPV | 87.0 [66.4, 97.2] | |
| FPER | 25.9 [11.1, 46.3] | |
| FNER | 8.3 [ 1.8, 22.5] | |
| Accuracy | 84.1 [72.7, 92.1] | |
| 11 Serotype Response | ||
|---|---|---|
| 4 Serotype Response | Responder (≥70% Positive) | Non-responder (<70% Positive) |
| Responder (≥70% Positive) | 33 | 7 |
| Non-responder (<70% Positive) | 3 | 20 |
| Diagnostic Agreement Summary | ||
| Diagnostic Parameter | Estimate [95% CI] | |
| Sensitivity | 91.7 [77.5, 98.2] | |
| Specificity | 74.1 [53.7, 88.9] | |
| PPV | 82.5 [67.2, 92.7] | |
| NPV | 87.0 [66.4, 97.2] | |
| FPER | 25.9 [11.1, 46.3] | |
| FNER | 8.3 [ 1.8, 22.5] | |
| Accuracy | 84.1 [72.7, 92.1] | |
We initially analyzed responses in 39 subjects who received PPSV23 but no prior PCV. We analyzed diagnostic agreement between the responsiveness as determined by evaluating all 23 serotypes compared with the 11 unique serotypes not found in PCV13 or those 4 unique serotypes not found in PCV20. When comparing 23 serotypes to 11 serotypes, we found the accuracy to be 81%. When comparing 23 serotypes to 4 serotypes, we found the accuracy to be 82%. For 63 subjects who previously received PCV13, we examined the diagnostic agreement between the 11 serotype and 4 serotype panels and found the accuracy to be 84%.
Even in subjects who have previously received PCV13 or PCV20, there is still diagnostic utility in administration of PPSV23 and evaluation of the response to the unique serotypes as a means of assessing anti-polysaccharide antibody responses.
