Threshold protective levels of serum IgG to Shigella lipopolysaccharide: re-analysis of Shigella vaccine trials data

A Shigella flexneri 2a synthetic glycan-based vaccine induces a long-lasting immune response in adults

“…Assessing the functionality of SF2a LPS-specific antibodies is an important tool for determining the mechanistic capabilities of anti-Shigella LPS serum IgG as a correlate of protection against shigellosis in the process of a Shigella candidate vaccine development 24,25 . The functionality of the specific SF2a-TT15induced antibodies evidenced in the phase I study up to 3 months after the third and last vaccination 39 was long-lasting as documented by the avidity and SBA results in sera of volunteers examined 2 and/or 3 years following vaccination.…”

“…Efficacy was originally demonstrated for a S. sonnei detoxified LPS-recombinant exotoxin A from Pseudomonas aeruginosa (dLPS-rEPA) conjugate in young Israeli soldiers 22 and subsequently in Israeli children down to 3 years of age 23 . These studies were critical for establishing serum IgG anti-LPS as a correlate of protection against shigellosis 24,25 . Moreover, they guided the development of a diversity of second generation injectable mono-and multivalent glycoconjugates and of other O-SP-based Shigella vaccine candidates aiming to generate protective immunity in the target population of infants in LMICs.…”

Towards establishing a correlate of protection against shigellosis: assessing immunological endpoints across immune responses to the Shigella sonnei 1790GAHB GMMA investigational vaccine

“…Immunomarker-derived VE (VE IM ) was calculated using data from the US adults in the CHIM study, based on the proportion of participants vaccinated with 1790GAHB with S. sonnei LPS serum IgG levels below the protection threshold of 1:1600 proposed by Cohen et al 13 A cut-off of 396 ELISA units (EU)/mL in the GSK Vaccines Institute for Global Health (GVGH) assay was established as the equivalent of this threshold from the Tel Aviv University (TAU) assay. This cut-off did not completely predict protection as 5/27 (18.5%) of participants vaccinated with 1790GAHB who developed shigellosis had anti-S. sonnei LPS serum IgG ≥ 396 EU/mL at the pre-challenge timepoint (D57).…”

“…Notes: 396 EU/mL in the current GSK Vaccines Institute for Global Health enzyme-linked immunosorbent assay used is equivalent to the 1:1600 titer in the Tel Aviv University assay. 13 Sensitivity was calculated as the number of participants with shigellosis and S. sonnei LPS serum IgG levels below the threshold over the total number of participants with shigellosis. Speci city was de ned as the number of participants without shigellosis and S. sonnei LPS serum IgG levels equal to or above the threshold over the total number of participants without shigellosis.…”

“…[10][11][12] More recently, the role of anti-LPS serum IgG as a CoP has been reinforced: in a re-analysis of serologic and vaccine e cacy (VE) data from a trial of the S. sonnei OAg-Pseudomonas aeruginosa recombinant exoprotein A glycoconjugate vaccine, a threshold of ≥ 1:1600 titer was associated with reduced risk of shigellosis and predicted VE against S. sonnei shigellosis in young Israeli adults. 13 Other potential CoPs include functional serum antibodies, mucosal antibodies produced by gut-homing lymphocytes, antibody-secreting cells (ASCs), and antibodies secreted in culture supernatants by lymphocytes isolated from peripheral blood mononuclear cells (PBMC) collected 7-10 days following exposure to Shigella. [14][15][16][17][18][19][20][21] The Generalized Modules for Membrane Antigens (GMMA) are outer membrane particles derived from genetically modi ed Gram-negative bacteria that have been proposed as a platform for OAg delivery.…”