Ben J. M. Zegers

Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study.

BACKGROUNDnPneumococcal conjugate vaccine prevents recurrent acute otitis media (AOM) in infants immunised at 2, 4, 6, and 12-15 months of age. We aimed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM.nnnMETHODSnIn this double-blind, randomised study, we enrolled 383 patients aged 1-7 years who had had two or more episodes of AOM in the year before entry. Randomisation was stratified in four groups according to age (12-24 months vs 25-84 months) and the number of previous AOM episodes (two or three episodes vs four or more episodes). Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine, or hepatitis A or B vaccines. They were followed up for 18 months for recurrence of AOM. We also cultured samples of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination.nnnFINDINGSnWe noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls (intention-to-treat analysis: rate ratio 1.25, 95% CI 0.99-1.57). Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations, immediate and complete replacement by non-vaccine pneumococcal serotypes took place.nnnINTERPRETATIONnThese data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM.

Infant B cell responses to polysaccharide determinants

Newborns and infants up to the age of 1.5-2 years of age are unable to produce antibodies to bacterial capsular polysaccharides. As a consequence, children up to the age of 2 years have an increased susceptibility for infections with encapsulated bacteria. Capsular polysaccharides are classified as so-called T cell independent type 2 antigens and induce IgG2 antibodies. The mechanism of B lymphocyte activation by polysaccharides differs from that of protein antigens and involves co-stimulation by CD21 (type 2 complement receptor). Reduced expression of CD21 on neonatal B lymphocytes can explain unresponsiveness to polysaccharides. Polysaccharide protein conjugates have the ability to overcome unresponsiveness to polysaccharides early in life. The response induced is predominant IgGl.

Defective antipneumococcal polysaccharide antibody response in children with recurrent respiratory tract infections

BACKGROUNDnRecurrent pyogenic infections are known to occur in patients with an impaired response to polysaccharide antigens. We investigated the occurrence of deficient responses to pneumococcal capsular polysaccharides in patients with recurrent respiratory tract and recurrent systemic infections.nnnMETHODSnForty-five patients, 1.7 to 17.1 years of age, were immunized with 23-valent pneumococcal polysaccharide vaccine. Antibody levels to seven pneumococcal serotypes (3, 4, 6A, 9N, 14, 19F, 23F) were determined by ELISA before and after immunization. In addition, patients received a booster immunization with diphtheria toxoid, tetanus toxoid, and poliomyelitis virus vaccine.nnnRESULTSnThirty-five patients had normal serum immunoglobulin levels. Five of these patients (14%) had low antipneumococcal preimmunization antibody levels and failed to respond to pneumococcal vaccination, whereas the response to booster immunization with protein antigens was appropriate. Three patients were younger than 3 years old, and one had a family history of IgG2 deficiency. Low IgG developed in a fifth patient during follow-up. Ten patients had a humoral immunodeficiency. Seven of these patients failed to respond to pneumococcal vaccination.nnnCONCLUSIONSnWe conclude that a defective immune response to polysaccharide antigens in patients requires long-term follow-up to distinguish transient maturational delay from a persistent selective impaired response to polysaccharide antigens, which on occasion may precede the development of humoral immunodeficiency disease.

Immunoglobulin isotype-specific antibody responses to pneumococcal polysaccharide vaccine in patients with recurrent bacterial respiratory tract infections

ABSTRACT: Anti-pneumococcal IgM, IgG1, IgG2, and IgA antibody titers were determined in 61 pediatric patients with recurrent bacterial respiratory tract infections. The patients were divided in those with normal serum Ig levels (group I, n = 46) and patients with dysimmunoglobulinemia (group II, n = 15). Antibody titers to five pneumococcal serotypes (3, 4, 6A, 9N, and 19F) of different immunogenicity were determined by ELISA, before and 14 d after immunization with pneumococcal polysaccharide vaccine. In the patients of group I, IgM responses did not vary between the various serotypes. IgG1 antibodies reached high levels for pneumococcal types 3, 4, and 9N compared with an adult reference hyperimmune plasma pool, but remained low for the weak immunogenic types 6A and 19F. IgG2 antibody titers remained low and were nearly absent in 20/46 patients. The fold increase in IgA was high, but the ultimate IgA antibody levels remained low. IgA levels remained low to absent in 10/46 patients. Two patients (4%) of group I failed to show anti-pneumococcal antibodies of all Ig isotypes. In group II, 6/15 patients (40%) made no anti-pneumococcal antibodies of any isotype, whereas the remaining patients made no IgG2 and/or IgA anti-pneumococcal antibodies. We conclude that the frequency of nonresponders to pneumococcal vaccination in patients with normal serum Ig is low (4%). However, low IgG2 anti-pneumococcal levels are found in approximately 50% of the patients. In patients with dysimmunoglobulinemia, IgA and IgG2 responses were absent in virtually all patients, whereas 40% made no anti-pneumococcal antibodies of any isotype.

Effects of insulin-like growth factors and growth hormone on the in vitro proliferation of T lymphocytes

The insulin-like growth factors I and II (IGF-I and IGF-II) promote proliferation and differentiation of many cell types. We report that recombinant IGF-I and IGF-II augment both the lectin- and anti-CD3-induced proliferation of human peripheral blood mononuclear cells (PBMC) at concentrations proportional to their binding affinities. IGF-I and IGF-II also augmented the lectin-induced proliferation of purified T lymphocytes. Effects of IGF-I were found in cultures of T cells vigorously depleted for monocytes and supplemented with saturating concentrations of interleukin-1. The latter results indicate that the effect of IGF-I on the proliferation of T lymphocytes can occur independent of monocytes or monocyte-derived factors.

Immunogenicity of a Streptococcus pneumoniae type 4 polysaccharide--protein conjugate vaccine is decreased by admixture of high doses of free saccharide.

In this study we report that the priming capacity of a Streptococcus pneumoniae type 4 polysaccharide-protein conjugate to booster immunizations with the native capsular polysaccharide is dose dependent. Furthermore, it is shown by admixture experiments that simultaneous administration of high doses of free saccharide (0.5-25 micrograms) of different chain lengths (varying from M(r) 1.6-120 kDa) decreases the anti-polysaccharide antibody response. Presence of low doses of saccharide (up to 10%), which are usually present in conjugates prepared by the carbodiimide coupling procedure, did not influence the anti-polysaccharide antibody response in adult and neonatal mice.

Pneumococcal Conjugate Vaccine Primes for Polysaccharide-Inducible IgG2 Antibody Response in Children with Recurrent Otitis Media Acuta

Children with frequent recurrent episodes of otitis media may have a deficient IgG2 antibody response to polysaccharide antigens. Five otitis-prone children were vaccinated with heptavalent pneumococcal conjugate vaccine. While all had an IgG1 antibody response to all pneumococcal serotypes included in the conjugate vaccine, the IgG2 response, especially to serotypes 6B, 9V, 19F, and 23F, was poor. However, vaccination with a 23-valent polysaccharide vaccine 6 months after conjugate vaccination induced an 11.5- to 163-fold increase in IgG2 anti-polysaccharide antibody titers. Thus, an IgG2 polysaccharide antibody deficiency can be overcome by priming with a pneumococcal conjugate vaccine followed by a booster with a polyvalent polysaccharide vaccine.

Pneumococcal conjugate vaccines.

We have prepared conjugates of pneumococcal type 4 polysaccharides (PS4) or oligosaccharides to tetanus toxoid using the carbodiimide method. The use of a spacer, 6-aminohexanoic acid, resulted in higher incorporation of carrier protein. Conjugates contained up to 10% free polysaccharide, but no free protein. In general, polysaccharide conjugates induced higher anti-PS4 IgG antibody titers than oligosaccharide conjugates. Conjugates with the highest amount of incorporated protein were the most immunogenic. The response to conjugated PS4 does show characteristics of a T cell-dependent antibody response, in terms of both isotype distribution and induction of immunological memory. Repeated immunization with high doses of PS4TT conjugate resulted in a virtually negative anti-PS4 IgG response, suggestive of the induction of high dose tolerance.

Ontogeny of the response of human peripheral blood T cells to glucocorticoids

The inhibitory effect of steroids such as dexamethasone on the immune response of adults has been widely documented. Little is known, however, about the effect of these agents on the developing immune system in newborns. The present study describes the ontogeny of the sensitivity of peripheral blood T cells to dexamethasone during the first year of life. Cord blood T cells of preterm or term infants appear to be extremely sensitive to inhibition of the proliferative response. This high sensitivity of cells to dexamethasone can still be observed in the first 2 weeks after birth. Subsequently, the sensitivity to dexamethasone inhibition of T-cell proliferation gradually decreases. At 1 year of age, the adult response pattern has been acquired.

T helper 2 cytokines induce preproenkephalin mRNA expression and proenkephalin A in human peripheral blood mononuclear cells

We investigated the regulatory influence of several cytokines on the expression of preproenkephalin (PPE) mRNA in human peripheral blood mononuclear cells (PBMC). By use of a quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), we demonstrate that the T helper 2 cytokines IL-4 and IL-10 are more potent in upregulating PPE mRNA expression in human PBMC than the T helper 1 cytokines IL-2 and gamma-IFN. In addition, TGF-beta is also an effective inducer of PPE mRNA. TGF-beta, IL-4 and IL-10 increase the cytoplasmatic concentration of met-enkephalin in PBMC. Secretion of met-enkephalin in the culture supernatant of IL-4- or IL-10-stimulated PBMC could not be observed, but proenkephalin A-derived met-enkephalin containing peptides could be demonstrated. IL-4 and IL-10 do not induce PPE mRNA via the same pathways. We could observe that PKA is involved in IL-4 mediated PPE mRNA induction, whereas IL-10 apparently uses another route.