Comparative immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugate vaccines
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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.
Key words:
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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Vaccinations with the 10-valent pneumococcal conjugated vaccine (PHiD-CV) started in Iceland in 2011. Protein D (PD) from H. influenzae , which is coded for by the hpd gene, is used as a conjugate in the vaccine and may provide protection against PD-positive H. influenzae .
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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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Neisseriaceae
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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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In October 2009, 7-valent pneumococcal conjugate vaccine (PCV7: PrevenarTM Pfizer) was replaced in the Northern Territory childhood vaccination schedule by 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; Synflorix™ GlaxoSmithKline Vaccines). This analysis aims to determine whether the reduced prevalence of suppurative otitis media measured in the PHiD-CV10 era was associated with changes in nasopharyngeal (NP) carriage and middle ear discharge (ED) microbiology in vaccinated Indigenous children. Swabs of the NP and ED were collected in remote Indigenous communities between September 2008 and December 2012. Swabs were cultured using standardised methods for otitis media pathogens. Children less than 3 years of age and having received a primary course of 2 or more doses of one PCV formulation and not more than one dose of another PCV formulation were included in the primary analysis; children with non-mixed single formulation PCV schedules were also compared. NP swabs were obtained from 421 of 444 (95 %) children in the PCV7 group and 443 of 451 (98 %) children in the PHiD-CV10 group. Non-mixed PCV schedules were received by 333 (79 %) and 315 (71 %) children, respectively. Pneumococcal (Spn) NP carriage was 76 % and 82 %, and non-typeable Haemophilus influenzae (NTHi) carriage was 68 % and 73 %, respectively. ED was obtained from 60 children (85 perforations) in the PCV7 group and from 47 children (59 perforations) in the PHiD-CV10 group. Data from bilateral perforations were combined. Spn was cultured from 25 % and 18 %, respectively, and NTHi was cultured from 61 % and 34 % respectively (p = 0.008). The observed reduction in the prevalence of suppurative OM in this population was not associated with reduced NP carriage of OM pathogens. The prevalence of NTHi-infected ED was lower in PHiD-CV10 vaccinated children compared to PCV7 vaccinated children. Changes in clinical severity may be explained by the action of PHiD-CV10 on NTHi infection in the middle ear. Randomised controlled trials are needed to answer this question.
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