Abstract
Humoral immune disorders such as common variable immunodeficiency (CVID) and specific antibody deficiency (SAD) are prevalent in clinical practice and require accurate functional testing of humoral immunity for diagnosis and to guide treatment approach. Traditionally, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been used to assess polysaccharide antibody responses by measuring pre- and post-vaccination pneumococcal titers. However, the recent introduction of pneumococcal conjugate vaccines (PCVs), such as PCV13, PCV15, and PCV20, into the childhood and adult vaccine schedules has significantly reduced the number of unique serotypes available for testing and in turn has complicated the evaluation process. We retrospectively analyzed serotype-specific antibody responses in patients aged 2–65 years who received PPSV23 at the University of Virginia Health System to compare diagnostic outcomes using all 23 serotypes versus the limited number of unique serotypes not included in prior PCVs—11 serotypes for PCV13 recipients and 4 for PCV20 recipients. Our findings demonstrate that although prior PCVs mean there is a reduced number of serotypes available for interpretation, PPSV23 testing maintains diagnostic accuracy between 81% and 84%. Despite limitations, the use of PPSV23 remains a valuable tool for identifying patients with clinically significant humoral immune deficiencies. In the future, alternative diagnostic approaches like Salmonella typhi polysaccharide vaccine response and opsonophagocytosis assays may become more commonly utilized as part of the evaluation of humoral immune disorders.
Keywords: Humoral immunodeficiency, Prevnar 20, specific antibody deficiency
Introduction
Humoral immune disorders are the most common inborn errors of immunity and thus are the most likely immune deficiencies to be encountered in clinical practice1. This group of disorders encompasses a broad range of both genetically and phenotypically defined conditions, including disorders such as common variable immunodeficiency (CVID) and specific antibody deficiency (SAD). SAD is defined as an impaired antibody response to polysaccharide antigens with normal immunoglobulin levels in patients two years or older with a history of recurrent otosinopulmonary infections2. CVID in comparison requires IgG level less than 2 standard deviations below age-appropriate reference range; a deficiency of IgA and/or IgM; impaired antibody response; age 4 years or greater; and absence of a secondary cause of hypogammaglobulinemia3 4. Management of both CVID and SAD includes maximizing medical management of comorbid medical conditions, early use of antibiotics, prophylactic antibiotics, and/or Ig replacement therapy (IgRT), depending on the clinical scenario5. In situations in which IgRT is deemed necessary, health insurers often require prescribers to submit documentation demonstrating laboratory evidence of impaired humoral immunity before coverage will be approved, thus placing an even greater emphasis on this element of the diagnosis. Specifically, this evidence typically requires demonstration of inadequate antibody responsiveness to vaccination.
Pneumococcal polysaccharide vaccine response
Currently, the most common functional testing of humoral immunity involves measurement of pre- and post-vaccination pneumococcal titers to assess polysaccharide antibody response to the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Vaccination with PPSV23 induces a T cell-independent antibody response. According to clinical practice guidelines, a protective or adequate response to an individual polysaccharide pneumococcal serotype is set at ≥1.3μg/mL along with a two- to four-fold increase in antibody titers from baseline levels6. A normal PPSV23 response for preschool children aged two to five years is defined as seroconversion of 50% or more of the serotypes tested, while a normal response in older children and adults ages six to sixty five years is defined as seroconversion of ≥70% of serotypes tested6. Reduced specific antibody responses can be further broken down into mild, moderate, or severe phenotypes according to current practice guidelines6. The severe phenotype in both children ages 2 - 5 years and adults 6 - 65 years is defined as having two or less protective titers following vaccination. Patients with the severe phenotype are often those with the most compelling clinical indications for the initiation of IgRT, while those with mild or moderate phenotypes in many cases may be successfully managed using other approaches as outlined in the introduction.
These guidelines, while widely used both in clinical practice and by health insurers, remain very controversial amongst practicing immunologists for a variety of reasons: certain pneumococcal serotypes have more immunogenicity than others; patients with higher preimmunization antibody titers are less likely to demonstrate a two-fold increase; and historical numerical cutoffs for protective titers are based on enzyme immunoassays6. These older assays have a poor correlation in the clinical setting to the multiplex bead assays which are most used currently7. In addition, the level necessary to be protective for infection may differ by serotype, anatomical site, and age7. These challenges of interpreting vaccine responses are even further confounded by an incredibly surprising degree of lab-to-lab variability in reporting responses to these vaccines8, 9. Indeed, it is quite important to appreciate that the cutoffs promulgated in these published guidelines were set more-or-less arbitrarily based almost entirely on expert opinion and reflecting the legitimate overarching need to have some sort of standard by which vaccine responses can be judged, as opposed to being based upon any compelling evidence10.
Pneumococcal conjugate vaccine response
Unlike PPSV23, pneumococcal conjugate vaccines (PCVs) are inactivated vaccines made from type-specific pneumococcal capsular polysaccharides linked to a carrier protein that triggers a T cell-dependent antibody response. This is especially important in regard to its ability to boost the vaccine’s effectiveness within the initial two years of life, but importantly, this enhanced efficacy does extend across the life span11, 12. In the United States, PCVs have been included as part of the standard childhood vaccination series since 2000 and, similarly PCVs are recommended in both older adults and adults with underlying risk for pneumococcal infections, including those with asthma or COPD13, 14. Of note, the clinical entity of anti-protein or anti-conjugate vaccine antibody deficiency is not yet clearly defined in clinical practice guidelines. A titer of ≥0.35 μg/mL after PCV was considered in initial licensing studies as protective against invasive infection, but laboratory cutoffs for defining normal titers following PCV vaccination still have not been defined for purposes of humoral immune evaluation15. It is important to point out that while anecdotal clinical experience suggests that many patients with severe anti-polysaccharide antibody deficiency also have poor response to conjugate vaccines, this has not been comprehensively studied to date.
Current challenges
In the last two years, the landscape of functional testing of humoral immunity has evolved to become more challenging for clinicians. There is widespread PCV13 vaccination in children and increasing PCV15 and PCV20 uptake in both children and adults. While essential for producing the desired protective immunity in these vaccine recipients, PCV-mediated responses are T-cell dependent and do not test the ability to mount a pure B-cell mediated anti-polysaccharide antibody response. Therefore, if a patient has received PCV (PCV7, PCV10, PCV13, PCV15, PCV20, and/or PCV21) in the past and then is given PPSV23 for diagnostic purposes, a pure B-cell response can only be assessed by examining those PPSV23 serotypes not included in the previously administered PCV (Table 1)10, 16. Clinicians are therefore left with attempting to interpret a response to a very limited number of serotypes (11 serotypes in patients who have received PCV13, 9 in those who have received PCV15, and only 4 in those who have received PCV20)17. PPSV23 itself is also becoming more challenging to locate as retail pharmacies discontinue it in favor of PCV.
Table 1.
Pneumococcal Vaccine Serotypes
| Serotypes | PCV7a | PCV13b | PCV15c | PCV20d | PCV21e | 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 | -- |
Abbreviations: PCV, pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine
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
Options remaining for clinicians include measuring pneumococcal titers following natural infection; measurement of response to the Salmonella typhi polysaccharide vaccine; administering PPSV23 (where available) to patients who have previously received PCV and relying on the limited number of unique serotypes to interpret polysaccharide antibody response; measurement of pneumococcal serotypes following PCV alone; or use of other functional assays of pneumococcal antibody responses.
Pneumococcal titers to natural infection
One option is measuring IgG titers of a specific pneumococcal serotype after a confirmed natural infection. This is not clinically practical for a variety of reasons: obtaining cultures to document microbial pathogen after otosinopulmonary infections is not routinely clinically indicated, and subtyping is not available at most centers5. Another option is obtaining pneumococcal antibody titers in patients who are naive to pneumococcal vaccination. If the patient exhibits protective antibody titers to multiple serotypes (although, again, the exact cutoffs for defining adequate “protection” have not been well defined), this would demonstrate the capability to generate antibody response to microbial-derived polysaccharides they have presumably been infected with and thus rules out humoral immune non-responsiveness. This approach also has limitations, however, namely that only a limited number of patients in the United States are unvaccinated, since pneumococcal vaccination has been available for adults in the United States since 198318 and as part of the routine childhood vaccine series since 200019.
Salmonella typhi polysaccharide response
Along with the PPSV23, the only other polysaccharide vaccine currently available in the United States is the Salmonella typhi (S typhi) vaccine (Typhim Vi, Sanofi Pasteur SA, Bridgewater, New Jersey), which is approved for use in patients 2 years or older. A normal serologic response to this vaccine is defined as a 2-fold or greater increase in titers after vaccination20. This vaccine has several theoretical advantages over the PPSV23 for the diagnosis of humoral immunodeficiency, including that it is a neo-antigen for most United States residents who have not been either previously infected or vaccinated 21. Furthermore, it can be used to evaluate polysaccharide vaccine response even in those patients currently receiving IgRT insofar as immunoglobulin donors are similarly also unlikely to have either been infected or vaccinated with S typhi, so titers are not present in IgRT preparations. However, there are significant practical limitations preventing more widespread use of this vaccine to evaluate humoral immunity outside of select academic centers, namely the lack of availability of quantitative testing outside of a single reference laboratory (Medical College of Wisconsin) and inconsistent payer coverage of vaccine administration and/or for laboratory testing. In addition, evaluation of the polysaccharide vaccine response to the Typhim vaccine is in some cases discordant with the results of polysaccharide vaccine challenge using PPSV23, which can lead to diagnostic uncertainty22, 23.
Opsonophagocytosis assays
Functional assays are designed to measure the quality rather than quantity of anti-pneumococcal antibody using multiplexed opsonophagocytosis assays. These assays have been developed and proposed as a superior means of evaluating pneumococcal antibody response, but these assays are not currently widely clinically available24.
Response to PPSV23 in patients who have received PCV13 or PCV20
As discussed previously, functional evaluation of humoral immunity in an era in which PCV20 (in adults) and PCV13 or PCV15 (in children) vaccination is widespread is increasingly challenging, as there are only a limited number of unique serotypes contained in PPSV23 that are not found in PCV (Table 1). Nonetheless, the authors’ clinical experience suggested that moderate to severe vaccine non-responsiveness would be diagnostically supported even when evaluating the response to only four or eleven serotypes.
To test this hypothesis, data were collected through a retrospective chart review using the electronic medical record. Inclusion criteria were patients ages 2 – 65 years seen at the University of Virginia Health Adult or Pediatric Immunodeficiency Clinic who received PPSV23 and had pneumococcal titers measured within 8 weeks of vaccination. Data extraction included previous pneumococcal vaccinations, specifically the types and dates of prior vaccinations administered (PCV7, PCV13, PPSV23). Pneumococcal titers were measured using a 23-serotype bead-based multi-plex immunoassay panel performed at Mayo Clinic Laboratories (Rochester, Minnesota). A protective response was defined as ≥1.3μg/mL. Subjects were defined as being “responders” to PPSV23 based on having a protective response to ≥70% of the serotypes analyzed. Statistical analysis was performed to assess in a pairwise manner, inter-serotype-panel diagnostic agreement among 4, 11, and 23 serotype pneumococcal antibody panel. Note, for the 23 serotype panel versus the 11 serotype diagnostic agreement analyses and for the 23 serotype panel versus the 4 serotype panel diagnostic agreement analyses, the 23 serotype panel findings served as the reference (“gold”) standard, while for the 11 serotype panel versus the 4 serotype panel diagnostic agreement analyses, the 11 serotype panel findings served as the reference standard. Diagnostic accuracy was calculated with confidence interval constructed based on the binomial exact method.
As expected, and pointing again to the challenges of using PPSV23 as a validated standard to assess humoral immune responsiveness, individual serotype-specific antibody responses revealed highly variable immunogenicity among the serotypes. As examples, serotypes 19F (97.4% protective), 22F (97.4%), and 23F (94.9%) were highly immunogenic while serotypes 12F (43.2%) and 4 (53.8%) were less immunogenic.
We initially analyzed responses in 39 subjects who had received PPSV23 but no prior PCV (Table 2). We defined patients as responders (a protective response to ≥70% of the serotypes) or non-responders. We compared results found when analyzing all 23 serotypes contained in PPSV23 (“23 serotype response”) in comparison to only the 11 unique serotypes not found in PCV13 (“11 serotype response”) (Table 2, top). Using the 23 serotype response, 27 subjects were classified as responders and 12 as non-responders. Using the 11 serotype response, 23 subjects were classified as responders and 16 as non-responders. Importantly, no subjects who would have been classified as a non-responder (i.e. having a humoral immune deficiency) using 23 serotypes were classified as responders (i.e. normal) using 11 serotypes (i.e. no false negatives). We then compared the 23 serotype response to those 4 unique serotypes not found in PCV20 (“4 serotype response”) (Table 2, middle). Using the 4 serotype response, 24 were classified as responders and 15 as non-responders. In this instance, 2 subjects who would have been classified as having a deficient specific antibody response using 23 serotypes, were instead classified as normal using 4 serotypes (i.e. 2 false negatives).
Table 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 |
| 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 |
| 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 |
| Accuracy | 84.1 [72.7, 92.1] | |
Next, for 63 subjects who had previously received PCV13, we examined the diagnostic agreement between the 11 serotype and 4 serotype responses (Table 2, bottom). Using the 11 serotype response, 36 subjects were classified as responders and 27 as non-responders. Using the 4 serotype response, 40 were classified as responders and 23 as non-responders. As a result, seven subjects who would have been classified as having a deficient vaccine response using 11 serotypes were classified as normal using 4 serotypes (false negative), while 3 who would have been classified as normal using 11 serotypes were classified as humoral immune non-responsive using 4 serotypes (false positive).
In summary, the diagnostic accuracy in each of these scenarios was surprisingly robust with few false negatives and suggests that, in subjects who have previously received PCV13 or PCV20, there is still diagnostic utility in administered PPSV23 and analyzing responsiveness to the 11 or 4 unique serotypes, respectively.
Conclusion
In this review we have summarized current limitations in our ability to assess humoral immune responses in patients suspected of having SAD or CVID. We would argue that the most widely available approach in the PCV era remains to perform the PPSV23 challenge and focus on the unique serotypes not present in any previously administered conjugated vaccine. As displayed in Table 2, the diagnostic accuracy of this approach ranges between 81 – 84%. This outcome reassuringly argues that even in subjects in whom even the PCV20 has previously been administered, there is still diagnostic utility in utilizing the PPSV23 and evaluating the response to as few as those 4 remaining unique serotypes. Unfortunately, PPSV23 vaccine availability is now increasingly limited at retail pharmacies and there is concern that its production may be discontinued entirely in the future. We hope that these observations will lend support to the argument that PPSV23 should be preserved as a tool for the functional evaluation of humoral immune defects.
It can well be argued that humoral immunodeficiency can be best diagnosed by an experienced clinical immunologist on the basis of a compelling medical history of well documented recurrent acute otosinopulmonary infections resulting from laboratory-proven infections with encapsulated bacteria5 in a patient with a constellation of supportive laboratory findings. For CVID, supportive laboratory findings include a low IgG and low IgA and/or IgM as required by consensus diagnostic criteria4 but also can include a very low/undetectable serum IgE25 or reduced classed switched memory B cells26. We would argue that the finding of an impaired polysaccharide vaccine response alone is neither necessary nor sufficient for establishing the diagnosis. Indeed, in many cases vaccine response testing is often just an expensive and gratuitous exercise merely performed in response to or in anticipation of an insurance provider’s request. From this standpoint, then, the recent challenges that have arisen to the use of PPSV23 to establish polysaccharide antibody non-responsiveness may represent a blessing in disguise, i.e., an opportunity for the clinical immunology community to partner with diagnostic laboratories to establish better validated, novel approaches to the functional testing of humoral immunity.
Key Messages.
Testing for humoral immune responses in patients suspected of having common variable immune deficiency or specific antibody deficiency requires the use of unconjugated polysaccharide vaccines and most commonly utilizes the 23-valent pneumococcal polysaccharide vaccine (PPSV23).
The implementation of pneumococcal conjugate vaccines (PCVs) reduces the number of available serotypes that can be interrogated for assessing PPSV23-based responses.
Despite serotype overlap among PCVs and PPSV23, PPSV23 retains its diagnostic value even when only a limited number of unique serotypes are assessed, for example, for the unique serotypes in individuals who previously received PCV20.
Preserving PPSV23 availability is crucial for diagnosis of humoral immune deficiencies in the current vaccination landscape as alternative testing methods, such as the Salmonella typhi polysaccharide vaccine, face practical limitations and are not widely accessible for clinical use
There is an urgent need to develop innovative diagnostic approaches to effectively assess humoral immunity as vaccination protocols continue to evolve
Funding Source:
National Institutes of Health: UO1 R56 AI158519 and RO1: AI175232
Abbreviations:
- CVID
Common variable immunodeficiency
- IgRT
Ig replacement therapy
- NPV
negative predictive value
- PCV
pneumococcal conjugate vaccine
- PPSV23
23-valent pneumococcal polysaccharide vaccine
- PPV
positive predictive value
- SAD
Specific antibody deficiency
Footnotes
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Conflicts of Interest: None
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