Immunogenicity of a Streptococcus pneumoniae type 4 polysaccharide-protein conjugate vaccine is decreased by admixture of high doses of free saccharide
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Objective To prepare conjugate vaccines by covalently coupling group C meningococcal polysaccharides (CPS) of different molecular sizes and tetanus toxioid (TT),and to determine their immunogenicity in mice.Methods CPS was degraded into different size fragments and conjugated to TT after activated by carbodiimide (EDAC) or cyanogen bromide (CNBr) to prepare conjugate vaccines (CPS-TT).NIH mice were immunized with these conjugate vaccines and both serum anti-CPS and antiTT IgG were determined by ELISA.Results Derivation rates and yields of degraded CPS activated by EDAC were higher than those of degraded CPS activated by CNBr,with 3.9％-5.7％ vs.0.4％-1.2％ and 11.4％-21.3％oo vs.2.4％-11.5％,respectively.CPS-TT prepared with degraded CPS activated by either EDCA or CNBr were all highly immunogenic in mice,but anti-CPS antibody levels in mice immunized with CPS-TT prepared with degraded CPS activated by EDCA were higher than those in mice immunized with CPS-TT prepared with degraded CPS activated by CNBr.Conclusion Degraded CPS activated by EDAC can be used to prepare group C meningococcal polysaccharide conjugate vaccine.
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Neisseria meningitidis,serogroup C; Polysaccharides,bacterial; Vaccines,conjugate; Immunogenicity
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Coupling T-cell-independent antigens such as the capsular-polysaccharide (PRP) of H. influenzae type b (HIB) to a T-cell-dependent protein-carrier enhances the immune response, particularly in individuals who are poor responders to such antigens. An adequate immunogenicity is dependent upon the characteristics of the PRP antigen, the protein carrier, the efficiency of conjugation and the stability of the conjugate. Since adequate immunogenicity tests are not available, stability studies in such products are essentially confined to molecular size distribution and determination of the degree of conjugation. A better understanding of the factors involved in stability and an improvement of the testing methods are highly desirable.
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Streptococcus pneumoniae is a major respiratory pathogen responsible for many diseases in young children and elderly. Because of the increasing antibiotic resistance of pneumococci recently, the need for development of an effective vaccine is more and more urgent. Since the 7-valent conjugate vaccine was licensed in the United States in 2000, its efficacy has been widely recognized. Effort on researching polysaccharide-protein conjugate vaccine never stopped. This article reviewed the conjugate vaccines in view of the carrier proteins. Key words: Conjugate vaccine, Streptococcus pneumoniae, capsular polysaccharide, carrier protein.
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Objective To prepare conjugate vaccine of the experimental group B streptococcal capsular polysac-charide-protein and evaluate its immunogenicity. Methods The purified type Ⅲ CPS were conjugated to tetanus toxoid (TT) with CNBr as an activator, EDAC as a couple agent, ADH as a spacer, to Prepare vaccine. Mice were immunized with these conjugates vaccine subcutaneously. Specific Antibody IgG to type Ⅲ CPS was measured with ELISA. Results All of the CPS - protein conjugates were superior to unconjugated CPS in eliciting CPS - specific immune responses in serum. Conclusion TT as a carrier protein for GBS Ⅲ CPS could markedly boost the immunogenicity of CPS.
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Various glycoprotein conjugate vaccines have been developed for the prevention of invasive meningococcal disease, having significant advantages over pure polysaccharide vaccines. One of the most important features of the conjugate vaccines is the induction of a T-cell dependent immune response, which enables both the induction of immune memory and a booster response after repeated immunization. The nature of the carrier protein to which the polysaccharides are chemically linked, is often regarded as the main component of the vaccine in determining its immunogenicity. However, other factors can have a significant impact on the vaccine's profile. In this review, we explore the physico-chemical properties of meningococcal conjugate vaccines, which can significantly contribute to the vaccine's immunogenicity. We demonstrate that the carrier is not the sole determining factor of the vaccine's profile, but, moreover, that the conjugate vaccine's immunogenicity is the result of multiple physico-chemical structures and characteristics.
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Objective To investigate the technological stability and immunogenicity of group C meningococcal polysaccharidetetanus toxoid(GCMP-TT) conjugate vaccine.Methods Eight batches of GCMP-TT conjugates were prepared on a large scale by using adipic dihydrazide(ADH)as the spacer and 1-ethyl-3(-3-dimethylaminopmpyl)carbodiimide(EDAC)as the coupling agent.The main characteristics of GCMP-AH derivatives and GCMP-TT conjugates were assessed by biochemical and immunological assays.NIH mice were immunized with the 8 batches of conjugates respectively,and determined for specific IgGs against GCMP and TT in sera by ELISA to evaluate the immunogenicity.Results All the 8 batches of GCMP-AH derivatives and GCMP-TT conjugates showed high antigenicities,of which the biochemical indexes were basically in agreement with little difference between batches,and met the requirements in European Pharmacopoeia(7th Edition).High specific IgG titers against GCMP and TT were elicited in sera of immunized mice,which showed significant difference with those elicited by CGMP(P 0.001).The IgG levels elicited after the 2nd and 3rd doses of GCMP-TT conjugates were significantly higher than that by the 1st dose(P 0.001).Conclusion The production procedure of GCMP-TT conjugate was stable and reliable,and the prepared conjugates showed high immunogenicity,which provided an important basis for large scale production of meningococcal conjugate vaccines.
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A physicochemical and immunological study of the stability of three different meningococcal (Men) ACWY conjugate vaccines was performed to evaluate any patterns of serogroup oligo- or polysaccharide-specific or carrier protein-specific stability that would affect immunogenicity. Critical quality and stability-indicating characteristics were measured, with the study supporting the suitability of both HPLC-SEC and HPAEC-PAD methods to detect changes following inappropriate vaccine storage. All three final products, ACWY-CRM197, -DT and -TT conjugate vaccines had expected quality indicator values and similar immunogenicity in a mouse model (anti-PS IgG and rSBA) when stored at +2-8°C. When stored at ≥+37°C, all conjugated carrier proteins and serogroup saccharides were affected. Direct correlations were observed between the depolymerization of the MenA saccharide as evidenced by a size-reduction in the MenA conjugates (CRM197, DT and TT) and their immunogenicity. MenA was the most labile serogroup, followed by MenC; then MenW and Y, which were similar. At high temperatures, the conjugated carrier proteins were prone to unfolding and/or aggregation. The anti-MenC IgG responses of the multivalent conjugate vaccines in mice were equivalent to those observed in monovalent MenC conjugate vaccines, and were independent of the carrier protein. For any newly developing MenACWY saccharide-protein conjugate vaccines, a key recommendation would be to consider the lyophilization of final product to prevent deleterious degradation that would affect immunogenicity.
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Background: Few data are available concerning the long term immunogenicity of the pediatric doses of hepatitis B vaccines given to preteenagers. The long term effect of the booster dose in teenagers is unknown. We evaluated the immunogenicity of 2 pediatric hepatitis vaccines after primary vaccination and after a booster dose. Methods: A prospective 15-year follow-up study of the immunogenicity of 2 hepatitis B vaccines was initiated in 1995 in Quebec City, Canada. One year apart, 1129 children 8–10 years old received Engerix-B 10 μg (EB), and 1126 received Recombivax-HB 2.5 μg (RB) vaccine after a 0-, 1-, 6-month schedule. After 5 years, one-third of the 2 cohorts were randomly selected. A booster dose of EB 10 μg or RB 5 μg was administered according to the vaccine used in the primary immunization. Antibodies were measured before, 1 month after and 1 year after the booster injection. Results: Before the booster dose, anti-HB surface antibody (HBs) was detected in 94.7% of the EB subjects and in 95.2% of the RB subjects (P = 0.85). The geometric mean titer (GMT) was higher in the EB than in the RB group (252 mIU/mL versus 66 mIU/mL, P < 0.0001). One month after the booster, 99.7% of subjects in the EB group and 99.6% in the RB group had a detectable anti-HBs, and 99.0 and 99.3%, respectively, had anti-HBs ≥10 mIU/mL. The anti-HBs GMT was 113,201 mIU/mL in the EB and 16,623 mIU/mL in the RB groups (P < 0.0001). One year after the booster, 99.3% of subjects in the EB group and 100% in the RB group had detectable anti-HBs, and 97.9 and 98.5% respectively, had anti-HBs ≥10 mIU/mL. The anti-HBs GMT was 14,028 mIU/mL in the EB and 3437 mIU/mL in the RB group (P < 0.0001). Conclusions: The immunity persists for at least 5 years after the primary vaccination with both pediatric vaccines in 99% of children vaccinated at the age of 8–10 years. It confirms that no booster is needed at that point.
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