Oligosaccharide-protein conjugate vaccines induce and prime for oligoclonal IgG antibody responses to the Haemophilus influenzae b capsular polysaccharide in human infants.

Abstract

hnmunity to Haemophilus influenzae type b can be mediated by serum antibody to the capsular polysaccharide (CP) 1 (1). Immunization of human adults and older children with isolated CP induces antibody; however, immunization of young infants fails to induce an antibody response (2, 3). The antibody response is inconsistent, nonboostable, low in titer, and nonprotective in children younger than ~18 mo of age. Children above that age can mount a protective antibody titer, but its magnitude remains less than the adult's until ~4 y of age. The cellular basis of antibody unresponsiveness and the delay of high-magnitude responses is unknown. In an effort to convert the CP to a more thymus-dependent (TD) immunogen, oligosaccharides prepared from the CP (4-6) or the CP itself (7, 8) have been presented with protein carriers. When the oligo conjugate was injected sequentially at ages 2, 4, and 6 mo, a mainly IgM primary and IgG secondary anti-CP antibody response was induced (5). In infants thus primed, titers could be further boosted by immunizing with isolated CP, even at an age normally unresponsive to CP vaccine (5). To elucidate the basis, at the B cell clonal level, of the increased antibody titer induced by the conjugate, and of the accelerated age-acquisition of responsiveness to the isolated CP, we have analyzed IEF patterns of serum antibody of the IgG isotype. Materials and MethodsVaccines. The conjugate vaccine was composed of oligosaccharides 3-10 repeating units in length (derived by hydrolysis of the H. influenzae b CP), coupled by reductive amination to diphtheria toxoid or the antigenically related nontoxic protein, CRM 197 (4). The conjugates contained -4% saccharide and 96% protein, wt/wt (4, 5). The dosage was 25/lg protein injected s.c. Purified CP (2) was later given to some subjects (a 10-ug s.c. injection). The age of the vaccinees and the intervals between vaccination are noted below.Antibody Quantitation. Serum antibody to the H. influenzae b CP was measured in a Farr-type radioantigen binding assay using [ H]CP, and calibrated with standard antiserum SK (Office of Biologics, U.S. Food and Drug Administration) as described (9).

IgG Subclass Response to Immunization with Haemophilus influenzas Type b Polysaccharide-Outer Membrane Protein Conjugate Vaccine1

“…Conceivably, in unprimed individuals, the conjugate vaccine primarily evokes IgGl re-sponses, whereas primed individuals show both IgGl and IgG2 responses. Whether the predominance of IgGl responses of the infants and older children to the primary immunization with the conjugate reflects lack of activation of B cell subsets specific for IgG2 or lack of isotype switching to IgG2 by the activated B cells cannot be distinguished by the present data (14,32).…”

“…Although not examined directly, the IgG2 responses of the children to the booster injection could result from stimulation of new B cell clones or activation of a subclass switch from IgGl to IgG2. To date, the only available data addressing this question are those of Insel and Anderson (32). They analyzed the clonal diversity of IgG antibody induced by immunization of infants with an Hib oligosaccharide-protein conjugate vaccine, followed by boosting with Hib PS vaccine.…”

A major crossreactive idiotype associated with human antibodies to the Haemophilus influenzae b polysaccharide. Expression in relation to age and immunoglobulin G subclass.

“…This finding suggests that before vaccinae-induced antibodies indicates restricted V re-tion this CRI-negative group had been exposed to either Hib I is consistent with previous reports showing a or, more likely, to PS crossreactive with Hib PS. Thus, natural r of similar, isoelectrically resolvable anti-Hib exposure, presumably via the mucosal route, may selectively in unrelated individuals (12,13,29 (Fig. 4).…”

Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation

“…7,12,13 Polysaccharide conjugate vaccines have now been developed that link capsular polysaccharides to protein carriers and elicit enhanced antibody responses. [13][14][15][16] One such vaccine, a 7-valent pneumococcal conjugate vaccine, has recently been shown to prevent invasive pneumococcal disease in healthy infants (PCV7; Prevnar, Wyeth Lederle Vaccines, Wyeth Lederle Laboratories, Pearl River, NY). 17 In this study, we examined whether immunization with this 7-valent pneumococcal conjugate vaccine would be immunogenic in patients undergoing HCT and whether donor immunization would elicit early protective responses to vaccine doses administered within the first year of transplantation.…”