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

Abstract

Streptococcus pneumoniae (S. pneumoniae) strains colonize the nasopharynx and can cause mucosal infections in the upper airway and middle ear, pneumonias, and invasive infections like bacteremia, sepsis, and meningitis. Over 90 serotypes, defined by the structure of their capsular polysaccharides, are known. Twenty‐three of these serotypes cause most infections and several of these serotypes can develop antibiotic resistance. Susceptibility factors that increase the susceptibility to S. pneumoniae mucosal and invasive infections include all forms of primary and secondary antibody deficiencies. Many patients affected by one of these deficiencies benefit from the regular administration of human gamma globulin (IgG) preparations. Donors of plasma units used to prepare human IgG have varying concentrations of IgG antibodies against relevant S. pneumoniae serotypes. These antibodies are developed in response to colonization and common subclinical infections and by routine vaccination with S. pneumoniae polysaccharide vaccines. The presence of an adequate concentration of these protective antibodies against all prevalent serotypes needs to be determined to assure the effectiveness of human IgG. All presently available methods to assess IgG antibodies against S. pneumoniae capsular polysaccharides have advantages and pitfalls that are analyzed in this review. In vitro testing does not provide a complete or necessarily accurate measurement of the effectiveness of antibodies in vivo. For regulatory purposes, caution needs to be used in the interpretation of currently available assays that measure pneumococcal antibody levels. Monitoring S. pneumoniae infections in patients treated with IgG and tracing information about IgG lots used to treat these patients should be encouraged.

Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

“…Although there is general agreement that both complement and anti-pneumococcal antibodies contribute to opsonophagocytosis-mediated immune defense against S. pneumoniae ( 11 , 61 – 63 ), only limited data are available on the relative contribution of complement- and direct antibody-mediated opsonisation. To address this, we compared two physiologic opsonophagocytosis assays adapted from recently published methods.…”

Antibodies to vaccine antigens in pooled polyclonal human IgG products

“…22,23 Functional assays require viable target cells and/or phagocytes, which may be difficult to maintain and which are much more variable than isolated antigen molecules. 22,24 A priori, we expect that neutralization or killing assays will correlate well with protection against infection 25 and therefore are likely to be more informative than binding assays, which might be measuring antibodies against irrelevant antigens. In fact, however, all laboratory assays are model systems which are merely surrogates for protection.…”

“…In general, binding assays in which killed organisms or isolated antigen(s) are immobilized on a solid phase such as a plastic enzyme‐linked immunoadsorbent assay (ELISA) plate or a visible or fluorescent microparticle are generally more rapid, more reproducible and easier to standardize than are assays of biological functions such as neutralization (prevention of infection of cells in vitro) or opsono‐phagocytic killing . Functional assays require viable target cells and/or phagocytes, which may be difficult to maintain and which are much more variable than isolated antigen molecules . A priori, we expect that neutralization or killing assays will correlate well with protection against infection and therefore are likely to be more informative than binding assays, which might be measuring antibodies against irrelevant antigens.…”

Assuring immune globulin potency in a world of changing pathogen challenges

“…Considerable attention was given to S. pneumoniae because it has been a major cause of pneumonia and invasive disease in untreated and undertreated patients with PI. Test methods and standards have evolved since 2007, although some commercial assays yield conflicting results, and ELISA titers do not always correlate with functional opsonophagocytic assays . It was generally agreed that an opsonophagocytosis assay or a multiplex version of the opsonophagocytosis assay were most attractive, as they provide antibody functionality, are reproducible, and may be relatively stable over time.…”

“…Test methods and standards have evolved since 2007, although some commercial assays yield conflicting results, and ELISA titers do not always correlate with functional opsonophagocytic assays. [30][31][32] It was generally agreed that an opsonophagocytosis assay or a multiplex version of the opsonophagocytosis assay were most attractive, as they provide antibody functionality, are reproducible, and may be relatively stable over time. H. influenzae titers (by ELISA) were also stable across IG products in one study.…”