Chemistry of a new investigational quadrivalent meningococcal conjugate vaccine that is immunogenic at all ages

Bröker, Michael; Dull, Peter; Rappuoli, Rino; Costantino, Paolo

doi:10.1016/j.vaccine.2009.07.036

Cited by 78 publications

(58 citation statements)

References 55 publications

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“…As CRM 197 is a nontoxic mutant of the diphtheria toxin, it does not require detoxification using formaldehyde or glutaraldehyde, a process employed in the preparation of diphtheria toxoids that can cause extensive crosslinking of the carrier protein to accessory antigens, with significant epitope modification (3). Additional features of the vaccine-manufacturing process for MenACWY-CRM that may contribute to these differences in immune responses include the techniques for producing oligosaccharides within a prespecified size range, the chemical linker used in the conjugation process, and the selective conjugation chemistry.…”

Section: Discussionmentioning

confidence: 99%

Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra

Reisinger

Baxter

Block

et al. 2009

Clin Vaccine Immunol

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Neisseria meningitidis is a leading cause of bacterial meningitis in the United States, with the highest case fatality rates reported for individuals >15 years of age. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM 197 conjugate vaccine, MenACWY-CRM, to those of the licensed meningococcal conjugate vaccine, Menactra, when administered to healthy adults. In this phase III multicenter study, 1,359 adults 19 to 55 years of age were randomly assigned to one of four groups (1:1:1:1 ratio) to receive a single dose of one of three lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained at baseline and 1 month postvaccination were tested for serogroupspecific serum bactericidal activity using human complement (hSBA). The hSBA titers following vaccination with MenACWY-CRM and Menactra were compared in noninferiority and prespecified superiority analyses. Reactogenicity was similar in the MenACWY-CRM and Menactra groups, and neither vaccine was associated with a serious adverse event. When compared with Menactra, MenACWY-CRM met the superiority criteria for the proportions of recipients achieving a seroresponse against serogroups C, W-135, and Y and the proportion of subjects achieving postvaccination titers of >1:8 for serogroups C and Y. MenACWY-CRM's immunogenicity was statistically noninferior (the lower limit of the two-sided 95% confidence interval was more than ؊10%) to that of Menactra for all four serogroups, with the postvaccination hSBA geometric mean titers being consistently higher for MenACWY-CRM than for Menactra. MenACWY-CRM is well tolerated in adults 19 to 55 years of age, with immune responses to each of the serogroups noninferior and, in some cases, statistically superior to those to Menactra.

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Section: Discussionmentioning

confidence: 99%

Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra

Reisinger

Baxter

Block

et al. 2009

Clin Vaccine Immunol

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“…Most carbohydrates are poorly immunogenic and fail to induce longlasting memory response. In order to recruit T cell help, we conjugated 1 to carrier protein CRM 197 using the previously described di-N-succinimidyl adipate (DSAP) spacer (Brö ker et al, 2009(Brö ker et al, , 2011, generating tetrasaccharide 1-CRM 197 conjugate 22 (Figures S1A-S1C available online) Martin et al, 2013). To investigate the antigenic potential of tetrasaccharide 1, three groups of mice (n = 6) were immunized with different doses of conjugate 22 corresponding to 3 mg, 2 mg, and 1 mg of tetrasaccharide 1 in the presence of a human-approved adjuvant, Alum Alhydrogel (Alum) (Clements and Griffiths, 2002; Figure 4).…”

Section: Chemistry and Biologymentioning

confidence: 99%

Antigenic Potential of a Highly Conserved Neisseria meningitidis Lipopolysaccharide Inner Core Structure Defined by Chemical Synthesis

Reinhardt

Yang

Claus

et al. 2015

Chemistry & Biology

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Neisseria meningitidis is a leading cause of bacterial meningitis worldwide. We studied the potential of synthetic lipopolysaccharide (LPS) inner core structures as broadly protective antigens against N. meningitidis. Based on the specific reactivity of human serum antibodies to synthetic LPS cores, we selected a highly conserved LPS core tetrasaccharide as a promising antigen. This LPS inner core tetrasaccharide induced a robust IgG response in mice when formulated as an immunogenic glycoconjugate. Binding of raised mouse serum to a broad collection of N. meningitidis strains demonstrated the accessibility of the LPS core on viable bacteria. The distal trisaccharide was identified as the crucial epitope, whereas the proximal Kdo moiety was immunodominant and induced mainly nonprotective antibodies that are responsible for lack of functional protection in polyclonal serum. Our results identified key antigenic determinants of LPS core glycan and, hence, may aid the design of a broadly protective immunization against N. meningitidis.

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“…Our glycoconjugates consisted of the HIV-1 related carbohydrate antigens clustered onto the PAMAM dendrons and subsequently conjugated to CRM 197 , which is well known for its excellent properties as carrier for bacterial oligo-and polysaccharides and is widely used in licensed glycoconjugate vaccines [22,28,[34][35][36]. The antigens were formulated with the potent MF59 adjuvant, which was shown to be effective in boosting both cellular and humoral immune response and is commonly used for seasonal flu vaccination [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

“…PAMAMs appeared attractive, due to their potential low immunogenicity [19,20] and built-in surface functionalities, which provide multiple sites for sugar incorporation. The high-mannose oligosaccharide clusters have been coupled to CRM 197 , a non-toxic mutant of diphtheria toxin already extensively used as carrier for glycoconjugate vaccines in humans [21][22][23]. Formulated with the MF59 adjuvant, an oil-in-water buffered emulsion of 5% squalene, 0.5% Tween 80 and 0.5% Span 85 that has been shown to be effective for intramuscular immunization [24][25][26], the glycoconjugates were tested in rabbits and mice.…”

Section: Introductionmentioning

confidence: 99%

Preparation, characterization and immunogenicity of HIV-1 related high-mannose oligosaccharides-CRM197 glycoconjugates

et al. 2010

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The dense glycan shield on the surface of human immunodeficiency virus type 1 (HIV-1) gp120 masks conserved protein epitopes and facilitates virus entry via interaction to glycan binding proteins on susceptible host cells. The broadly neutralizing monoclonal antibody 2G12 binds a cluster of high-mannose oligosaccharides on the gp120 subunit of HIV-1 Env protein. This oligomannose epitope is currently being considered for the design of a synthetic vaccine. The cluster nature of the 2G12 epitope suggests that a multivalent antigen presentation is important to develop a carbohydrate-based vaccine candidate. In this work we describe the development of neoglycoconjugates displaying clustered HIV-1 related oligomannose carbohydrates. We exploited flexible polyamidoamine (PAMAM) scaffold to generate four- and eight-valent sugar clusters of HIV-1-related oligomannose antigens Man(4), Man(6) and Man(9). The multivalent presentation of oligomannoses increased the avidity of Man(4) and Man(9) to 2G12. The synthetic glycodendrons were then covalently coupled to the protein carrier CRM(197), formulated with the adjuvant MF59, and used to immunize two animal species. Oligomannose-specific IgG antibodies were generated; however, the antisera failed to recognize recombinant HIV-1 gp120 proteins. We conclude that further structural vaccinology work is needed to identify an antigen presentation that closely matches in vivo the structure of the epitope mapped by 2G12.

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Chemistry of a new investigational quadrivalent meningococcal conjugate vaccine that is immunogenic at all ages

Cited by 78 publications

References 55 publications

Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra

Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra

Antigenic Potential of a Highly Conserved Neisseria meningitidis Lipopolysaccharide Inner Core Structure Defined by Chemical Synthesis

Preparation, characterization and immunogenicity of HIV-1 related high-mannose oligosaccharides-CRM197 glycoconjugates

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