Immunogenicity in animals of a polysaccharide-protein conjugate vaccine against type III group B Streptococcus.
01 Nov 1990-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 86, Iss: 5, pp 1428-1433
TL;DR: The results suggest that this method of conjugation to a carrier protein may be a useful strategy to improve the immunogenicity of the type III group B Streptococcus polysaccharide in human subjects.
Abstract: The native capsular polysaccharide of type III group B Streptococcus elicits a specific antibody response in only 60% of nonimmune human subjects. To enhance the immunogenicity of this polysaccharide, we coupled the type III polysaccharide to tetanus toxoid. Prior to coupling, aldehyde groups were introduced on the polysaccharide by controlled periodate oxidation, resulting in the conversion of 25% of the sialic acid residues of the polysaccharide to residues of the 8-carbon analogue of sialic acid, 5-acetamido-3,5-dideoxy-D-galactosyloctulosonic acid. Tetanus toxoid was conjugated to the polysaccharide by reductive amination, via the free aldehyde groups present on the partially oxidized sialic acid residues. Rabbits vaccinated with the conjugate vaccine produced IgG antibodies that reacted with the native type III group B streptococcal polysaccharide (3/3 rabbits), while rabbits immunized with the unconjugated type III polysaccharide failed to respond (0/3 rabbits). Sera from animals receiving conjugate vaccine opsonized type III group B streptococci for phagocytic killing by human peripheral blood leukocytes, and protected mice against lethal challenge with live type III group B streptococci. The results suggest that this method of conjugation to a carrier protein may be a useful strategy to improve the immunogenicity of the type III group B Streptococcus polysaccharide in human subjects.
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TL;DR: A critical role of natural IgM in the immediate defense against severe bacterial infection is demonstrated and reconstitution with a monoclonal IgM specific to phosphatidylcholine, a conserved cell membrane component, has a modest effect.
Abstract: To evaluate the role of natural immunoglobulin (Ig)M in the immediate response against microbial infection, we tested mutant mice that are deficient in secreted (s)IgM in an acute peritonitis model induced by cecal ligation and puncture (CLP). 20% of wild-type mice died within 32 h of CLP, whereas 70% of sIgM-deficient mice died within the same time period. The increased susceptibility was associated with a reduced level of tumor necrosis factor (TNF)-α, a decreased neutrophil recruitment and an increased bacterial load in the peritoneum, and elevated levels of endotoxin and proinflammatory cytokines in the circulation. Resistance to CLP by sIgM-deficient mice was restored by reconstitution with polyclonal IgM from normal mouse serum. Reconstitution with a monoclonal IgM specific to phosphatidylcholine, a conserved cell membrane component, has a modest effect but a monoclonal IgM specific to phosphocholine is not protective. These findings demonstrate a critical role of natural IgM in the immediate defense against severe bacterial infection.
535 citations
Cites background from "Immunogenicity in animals of a poly..."
...The capsular polysaccharides also inhibit phagocytosis by macrophages and neutrophils (36)....
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TL;DR: Results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody, and implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.
Abstract: Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by approximately 50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of non-immune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.
511 citations
TL;DR: Invasive group B streptococcal infection is a major problem not only in pregnant women and neonates but also in nonpregnant adults, especially those who are elderly and those who have chronic diseases.
Abstract: Background Group B streptococci (Streptococcus agalactiae) are a major cause of meningitis and septicemia in neonates and pregnant women, but the importance of group B streptococcal disease in nonpregnant adults has not been clearly defined. Methods We conducted a prospective surveillance of the pathogens responsible for meningitis for a period of 24 months in 35 hospitals and a referral laboratory in metropolitan Atlanta. We reviewed the clinical and laboratory records of all the nonpregnant adults identified as having invasive group B streptococcal disease during this period. Results During 1989 and 1990 there were 424 patients with invasive group B streptococcal disease (annual incidence, 9.2 cases per 100,000 population). Of these patients, 46 percent were 1 month of age or younger, 6 percent were older than 1 month but younger than 18 years of age, and 48 percent were 18 or older. Men and nonpregnant women accounted for 68 percent (n = 140) of all cases among adults (annual incidence, 4.4 per 100,000...
451 citations
TL;DR: GBS can impair neutrophil defense functions by coopting a host inhibitory receptor via sialoglycan molecular mimicry, a novel mechanism of bacterial immune evasion.
374 citations
TL;DR: This Review describes a template that can be followed to develop vaccines against other bacterial pathogens and highlights efforts to identify GBS antigens that overcome serotype-specificity.
Abstract: An ongoing public health challenge is to develop vaccines that are effective against infectious diseases that have global relevance Vaccines against serotypes of group B Streptococcus (GBS) that are prevalent in the United States and Europe are not optimally efficacious against serotypes common to other parts of the world New technologies and innovative approaches are being used to identify GBS antigens that overcome serotype-specificity and that could form the basis of a globally effective vaccine against this opportunistic pathogen This Review highlights efforts towards this goal and describes a template that can be followed to develop vaccines against other bacterial pathogens
333 citations
References
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TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
TL;DR: In this article, a method was developed to determine submicro amounts of sugars and related substances using a phenol-sulfuric acid reaction, which is useful for the determination of the composition of polysaccharides and their methyl derivatives.
Abstract: Simple sugars, oligosaccharides, polysaccharides, and their derivatives, including the methyl ethers with free or potentially free reducing groups, give an orangeyellow color w-hen treated with phenol and concentrated sulfuric acid. The reaction is sensitive and the color is stable. By use of this phenol-sulfuric acid reaction, a method has been developed to determine submicro amounts of sugars and related substances. In conjunction with paper partition chromatography the method is useful for the determination of the composition of polysaccharides and their methyl derivatives.
45,381 citations
TL;DR: A new method for the quantitive determination of sialic acids is described, which is about 50% more sensitive than the orcinol-hydrochloric acid method generally used and considerably lower with the resorcin reagent.
2,741 citations
TL;DR: It is suggested that transplacental transfer of maternal antibody protects infants from invasive Group B streptococcal infection with Type III strains.
Abstract: We investigated the role of maternal antibody in neonatal Group B streptococcal infection with a radioactive antigen-binding assay employing a purified polysaccharide antigen with both Type III and Group B determinants. Serums from seven women who gave birth to infants who had invasive Group B streptococcal infection with Type III strains were all deficient in antibody. In contrast, serums from 22 of 29 pregnant Type III vaginal carriers whose infants were healthy contained antibody with a prevalence significantly different from that in women delivering infants with Type III disease (P < 0.01). Three healthy neonates born to women with antibody in serums had demonstrable antibody in umbilical-cord serum. These data suggest that transplacental transfer of maternal antibody protects infants from invasive Group B streptococcal infection with Type III strains. (N Engl J Med 294:753–756, 1976)
634 citations
TL;DR: The HIB Ps-protein conjugates induced serum anti-type b antibodies having bactericidal activity at levels shown to be protective in humans when low doses were injected subcutaneously in a saline solution, in contrast to the poor immunogenicity of the purified HIBPs in mice and rabbits.
Abstract: A method is presented for covalently bonding Haemophilus influenzae type b capsular polysaccharide (HIB Ps) to several proteins. The method is efficient and relies upon the use of adipic dihydrazide as a spacer between the capsular polysaccharide and the carrier protein. In contrast to the poor immunogenicity of the purified HIB Ps in mice and rabbits, the HIB Ps-protein conjugates induced serum anti-type b antibodies having bactericidal activity at levels shown to be protective in humans when low doses were injected subcutaneously in a saline solution. The antibody response in mice was related to the dose of the conjugates, increased with the number of injections, and could be primed by the previous injection of the carrier protein. The HIB Ps-protein conjugates were immunogenic in three different mouse strains. The importance of the carrier molecule for the enhanced immunogenicity of the HIB Ps-protein conjugates was shown by the failure of HIB Ps hybrids prepared with either the homologous polysaccharide or pneumococcus type 3 polysaccharide to induce antibodie in mice. Rabbits injected with the HIB Ps-protein conjugates emulsified in Freund's adjuvant produced high levels of serum anti-type b antibodies which induced a bactericidal effect upon H. influenzae type b organisms. It is proposed that the HIB Ps component of the polysaccharide protein conjugates has been converted to a thymic-dependent immunogen. This method may be used to prepare protein-polysaccharide conjugates with HIB Ps and other polysaccharides to be considered for human use.
623 citations