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Assessment of Serotype-Specific Streptococcus pneumoniae Antibodies

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Published: October 2013

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Streptococcus pneumoniae vaccines have been effective in reducing incidence of respiratory and invasive pneumococcal diseases. Quantitative measurement of IgG antibodies against polysaccharides present in these vaccines is useful in assessing the response to active immunization with nonconjugated and protein-conjugated vaccines and determining the ability of an individual to respond to the polysaccharide antigens. Assessment of serotype-specific Streptococcus pneumoniae antibodies is generally only needed as part of an evaluation for humoral or combined immunodeficiency, and not for routine assessment of vaccine responses.

Presenter: Melissa Snyder, PhD

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Before beginning this presentation, I want to confirm that I have no disclosures relevant to this topic.

There are several important take-home messages regarding utilization of testing for Streptococcus pneumonia antibodies.  First, assessment of serotype-specific antibodies for Streptococcus pneumoniae  antibodies is not needed for routine assessment of a healthy individual’s response to vaccination, but rather as part of a work-up for immunodeficiency, primarily humoral or combined immunodeficiencies.  Second, this testing is most useful, and allows for the most optimal interpretation, when used in the context of comparing prevaccine antibody concentrations to a postvaccine antibody response. 

Streptococcus pneumoniae is a gram-positive, encapsulated bacterium.  Although generally thought of as a diplococci, this bacteria can also be found singly or in larger chains, an example of which is shown in the picture on this slide.  The structure of the Streptococcus pneumoniae bacteria includes an inner cellular membrane, which is composed of a lipid bilayer, and a cell wall, which consists of cell wall C polysaccharide.  This polysaccharide is invariant across the various serotypes, which we will discuss in a moment, and induces antibodies which are not protective in terms of an immune response against Streptococcus pneumoniae .  Lastly, we have the outer capsule, which is composed largely of various polysaccharides. 

The polysaccharides present in the bacterial capsule define the various serotypes of Streptococcus pneumoniae.  To date, more than 90 serotypes of Streptococcus pneumoniae have been identified, again based on differences in the polysaccharides present in the bacterial capsule.  The characterization and identification of these serotypes is important, as there are critical differences in the behavior of these various serotypes.  Some serotypes are found more frequently in carriers of Streptococcus pneumoniae, while other serotypes are known to have a higher potential for invasive disease or antibiotic resistance.  Still other serotypes have been found to be more virulent, with a higher potential for transmission between individuals, something very important from a public health perspective.

Humans are the primary reservoir of Streptococcus pneumoniae , meaning that many individuals carry this bacterium without manifesting symptoms of an infection.  Carriage of the bacteria generally occurs within the nasopharynx area, and children in particular tend to be very robust carriers.  However, in some individuals, symptomatic infections caused by Streptococcus pneumoniae may manifest.  Some of the commonly associated respiratory infections include pneumonia and otitis media.  In fact, Streptococcus pneumoniae is one of the leading causes of community-acquired pneumonia.  In addition to infections of the respiratory tract, Streptococcus pneumoniae can lead to invasive disease as well, including septicemia, or infection of the bloodstream, and meningitis, in which the bacteria invades the central nervous system and is found in the cerebrospinal fluid.

There are some risk factors associated with risk of infection from Streptococcus pneumoniae.  These risk factors include age, specifically less than 2 years or greater than 65 years of age, male gender, or living in close contact with children under the age of 6 who routinely attend a day care facility.  Certain environmental exposures, including cigarette smoking and excessive alcohol use can also put individuals at increased risk for infection.  Lastly, increased frequencies of infections are also seen in individuals with certain coexisting medical conditions, such as chronic obstructive pulmonary disease and congestive heart failure, and neurological diseases, include seizure disorders.  And lastly, and probably not surprisingly, individuals with various primary or secondary immunodeficiencies are also at risk for infection with Streptococcus pneumoniae, including individuals with hypogammaglobulinemia, complement deficiency, or asplenia.

Luckily, there are interventions that have proven effectiveness in preventing diseases associated with Streptococcus pneumoniae infection.  Seasonal influenza vaccination is an indirect mechanism through which pneumococcal infections can be prevented.  Prevention of any respiratory tract infection, in particular influenza, leads to reductions in all-cause pneumonia, including pneumococcal disease.  In addition, a more direct vaccination strategy specific for Streptococcus pneumoniae is very effective in preventing infections.  This type of vaccination is now routinely recommended for children, adults over the age of 65 years, and other individuals with certain predisposing conditions as discussed on the previous slide.

There are several Streptococcus pneumoniae vaccines available for clinical use.  Pneumovax is a 23-valent polysaccharide vaccine, meaning that it contains polysaccharides present in the outer bacterial capsule from 23 different serotypes.  The polysaccharides in this vaccine are not conjugated, and induced a T-cell independent antibody response.  The issue with this type of nonconjugated polysaccharide vaccine is that it is generally not effective in children, specifically in children under the age of the 2 years.  This is because a young child’s immune response is not mature and has only weak responses to pure polysaccharides.  For this reason, Prevnar and Prevnar-13 were developed.  Prevnar is a 7-valent vaccine, while Prevnar-13 contains polysaccharides from 13 serotypes.  What distinguishes both Prevnar vaccines from Pneumovax is the fact that the polysaccharides are conjugated to a protein, specifically to CRM197, which is a diphtheria variant carrier protein.  By conjugating the polysaccharides to a protein carrier, now a T-cell dependent antibody response can be initiated, which is significantly more robust in children.

The serotypes present in each of the vaccines are shown in this table.  The serotypes included in the vaccines were originally chosen based on associations between the serotypes and risk of respiratory and invasive infections.  Pneumovax is still used routinely for vaccination of adults.  However, the 7-valent Prevnar has largely been replaced by Prevnar-13 for use in children.  Each of the serotypes found in the 7-valent Prevnar vaccine are also found in Pneumovax.  However, there is not a 100% overlap between Prevnar-13 and Pneumovax.  Specifically, the 6A serotype is found only in Prevnar-13.  In general, most studies have shown that, since introduction of routine pneumococcal vaccinations, the incidence of pneumococcal-related diseases has decreased.  This is true not only for individuals who are vaccinated, but also for unvaccinated individuals.  This phenomenon is known as the “herd effect”.  However, as vaccines have been effective in preventing disease associated with certain serotypes, other serotypes have emerged as public health concerns.  It is for this reason that pneumococcal vaccines will likely continue to evolve in terms of which serotypes are included both in the conjugated and nonconjugated versions.

One mechanism through which streptococcal pneumoniae vaccination is effective for an individual is the production of an antibody response.  The test “Streptococcus pneumoniae IgG Antibodies, 23 Serotypes, Serum” with the test ID PN23 is offered through Mayo Medical Laboratories.  This test can be used to quantitatively measure IgG antibodies that are specific for the 23 polysaccharides present in the Pneumovax vaccine.  This test is performed by multiplex immunoassay on a bead-based system.  For this test, individual fluorescent beads are conjugated to specific polysaccharides.  These various beads are then combined together to make a bead mixture.  Diluted patient serum is then added to the bead mixture.  If there are streptococcal pneumoniae antibodies present, the antibodies will bind to the specific polysaccharide on the bead.  The bound antibodies are then detected by the addition of a fluorescently labeled anti-human IgG.  The fluorescent signal from the anti-human IgG is detected and compared to a standard curve, allowing for quantitation.

The “Streptococcus pneumoniae IgG Antibodies, 23 Serotypes, Serum” test is useful for assessing the IgG antibody response that is generated by immunization with either the nonconjugated or conjugated vaccines.  It is primarily used for the assessment of individuals with a suspected humoral or combined immunodeficiency to determine their ability of produce antibodies to polysaccharides.

An important point to note is that, on July 2, 2013, a new reference range for the “Streptococcus pneumoniae IgG Antibodies, 23 Serotypes, Serum” test was implemented.  Prior to July 2, the reference range used for this test was based on analysis of a single serum sample from 100 healthy individuals with no history of pneumococcal vaccination.  The goal had been to identify a baseline concentration of antibodies in what essentially is an unvaccinated individual.  Recently, a study was completed at the Mayo Clinic in which prevaccine and postvaccine samples were obtained from 100 healthy individuals; these data serve as the basis for the new reference ranges. 

The new reference ranges should allow for improved interpretation of the results from this testing, due to the inclusion of both pre- and postvaccine samples.  However, it is important to remember that this test must be interpreted as a whole, and not on an individual serotype basis.  In other words, the results from all the serotypes must be evaluated together to make an overall interpretation of the test results.  Some general guidelines are presented here.  If considering the results from a single serum sample, having concentrations greater than or equal to the reference value for at least half of the serotypes is consistent with a normal response, presumably to a previous vaccination.  If both a pre- and postvaccine are available, then at least a 2-fold increase in concentrations for at half of the serotypes would be consistent with a normal immune response to the vaccination.  It must be remembered that evaluation of streptococcal pneumoniae antibody responses are only one part of the assessment of an individual with a suspected immunodeficiency.  As always, correlation of the antibody responses with clinical presentation, including history of recurrent infections, and other assessments of the immune system, including total immunoglobulin concentrations, cellular immunophenotyping, and functional cellular responses, is critical.

To conclude, there are various Streptococcus pneumoniae vaccines available for use in children and adults.  Both types of vaccines have been useful in reducing the incidence of respiratory and invasive pneumococcal disease, even for individuals who have not received the vaccination.  Streptococcal pneumoniae vaccines induce an antibody response, and assessment of these antibodies can provide information regarding a person’s ability to respond to polysaccharide antigens.  However, this is generally not required for all individuals who receive the vaccine, but rather as one part of the evaluation of those individuals with a suspected humoral or combined immunodeficiency.