Potential protective immunogenicity of tetanus toxoid, diphtheria toxoid and Cross Reacting Material 197 (CRM197) when used as carrier proteins in glycoconjugates

Abstract

When tetanus toxoid (TT), diphtheria toxoid (DT) or Cross Reacting Material 197 (CRM197), a non-toxic diphtheria toxin mutant protein, are used as carrier proteins in glycoconjugate vaccines, these carriers induce a protein specific antibody response as measured by in vitro assays. Here, it was evaluated whether or not glycoconjugates based on TT, DT or CRM197 can induce a protective immune response as measured by potency tests according to the European Pharmacopoeia. It could be shown, that the conjugate carriers TT and DT can induce a protective immune response against a lethal challenge by toxins in animals, while glycoconjugates based on CRM197 failed to induce a protective immune response. Opportunities for new applications of glycoconjugates are discussed.

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries

“…While vaccines conjugated to TT (used in Menitorix ® [MenC-TT/PRP-TT, GSK]) and DT (used in Menactra ® [Men ACWY-DT, GSK] and in Synflorix ® [PCV10, GSK]) have shown to induce immunity against TT or DT, vaccines using CRM 197 as the carrier protein (used in Prevnar13 ® [PCV13, Pfizer], Menveo ® [MenACWY-CRM, GSK], investigational trivalent GBS vaccine [GSK]) have not shown to induce immunity against DT 174 , 253 . The interest of inducing protection against tetanus through a TT-conjugated GBS vaccine could be considered where maternal and neonatal tetanus remain a concern.…”

Peer Review #3 of "Application of built-in adjuvants for epitope-based vaccines (v0.1)"

“…Helper epitopes selected from TT fragment C (TTFrC) are typically associated with the target epitope to stimulate a CD4+ T cell response (e.g., anti-brucellosis and anti-atherosclerosis multi-epitope vaccines) (Saadi et al, 2017;Tourani et al, 2017). TT is also commonly used as a carrier protein for glycoconjugate vaccines (Broker, 2016). For example, the Vi polysaccharide of typhoid has been combined with TT via chemical bonding to compare the immunogenicity with that of DT and CRM197 as a carrier protein (Arcuri et al, 2017).…”

“…⑵ LFn as the delivery carrier of ESAT-6 antigen. (Tobias et al, 2017;Zhang et al, 2016) (Saadi et al, 2017;Broker, 2016;Arcuri et al, 2017) ( Wesche et al, 1998;Shaw & Starnbach, 2008;Chandra et al, 2006 ) 3…”

Factors contributing to the immunogenicity of meningococcal conjugate vaccines

“…One dose of meningococcal conjugate vaccine based on TT (HibMenC-TT) was able to protect mice against a lethal challenge with tetanus toxin, and a conjugate vaccine based on DT (MenACWY-DT) was able to protect guinea pigs against a lethal challenge with diphtheria toxin. 34 However, even 2 doses of conjugate vaccines based on CRM 197 (MenC-CRM; MenACWY-CRM) failed to protect guinea pigs against a lethal challenge with diphtheria toxin. 34 It therefore appears that CRM 197 , which differs in one amino acid from diphtheria toxin (and DT), and has not been treated with formaldehyde, has lower immunogenic/protective capacity than DT, when used as carrier protein in meningococcal vaccines and assessed in guinea pigs.…”

“… 34 However, even 2 doses of conjugate vaccines based on CRM 197 (MenC-CRM; MenACWY-CRM) failed to protect guinea pigs against a lethal challenge with diphtheria toxin. 34 It therefore appears that CRM 197 , which differs in one amino acid from diphtheria toxin (and DT), and has not been treated with formaldehyde, has lower immunogenic/protective capacity than DT, when used as carrier protein in meningococcal vaccines and assessed in guinea pigs.…”