Fifth Percentile Cutoff Values for Antipneumococcal Polysaccharide and Anti-Salmonella typhi Vi IgG Describe a Normal Polysaccharide Response

Abstract

BackgroundSerotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking.ObjectiveTo establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA.MethodsOne hundred healthy subjects (10–55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3–4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method.ResultsApplying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and ¼ for anti-A.ConclusionWe establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.

Measuring quantity and function of pneumococcal antibodies in immunoglobulin products

“…Other thresholds have also been used for diagnostic purposes, including the 0.35 μg/mL threshold used in vaccine studies . Recent studies have also proposed serotype‐specific thresholds to identify subnormal responses to pneumococcal vaccines . For clinical diagnostic applications, antibody levels are generally measured using multiplex bead array (or “Luminex”) assays, since ELISA is impractical for measuring antibodies to many serotypes.…”

Overview of antibody‐mediated immunity to S. pneumoniae: pneumococcal infections, pneumococcal immunity assessment, and recommendations for IG product evaluation

“…Different laboratories operating in different regions of the world have established their own ranges of serotype‐specific antibody concentrations. Serotype‐specific threshold values could be applicable for some defined, uniform populations . However, for values obtained by different commercial and private laboratories this kind of definition of antibody responses is unrealistic, as it is influenced by prevalent infections and pneumococcal immunization practices …”

Immunoglobulin E—an Innocent Bystander in Host Defense?

“…The accurate differentiation of CVID from secondary antibody deficiency is particularly imperative because adequately substituted patients on average live some 30 years longer than historical controls. Giving IgG replacement therapy to for example asthmatics with steroid-induced hypogammaglobulinemia may cause severe side effects [5]. Despite a rather uniform phenotype, there are multiple and variable available diagnostic criteria for CVID [3,4].…”

“…Despite a rather uniform phenotype, there are multiple and variable available diagnostic criteria for CVID [3,4]. Much of this diagnostic confusion stems from variable cutoffs for normalcy used for immunoglobulin classes IgG, IgA, and IgM, as well as for specific antibodies, especially for polysaccharide responses against pneumococcal antigens [3][4][5]. Typically, CVID patients have low IgG, low IgA, and specific antibody deficiency.…”

“…As alternatives, anti-Salmonella antibody responses and serum allohemagglutinins have been used to help in the differential diagnosis of CVID. However, these sadly seem to perform suboptimally [5]. Recently, reduced levels of serum free light chains were also proposed to function as differentiation markers for CVID [6].…”