Vaccine designed for one Shigella strain shows unexpected protection against another

ABSTRACT Background Shigella flexneri 2a (SF2a) and 6 (SF6) are two of the most common S. flexneri serotypes. They have distant O-specific polysaccharide (O-SP) structures. Previous studies showed no cross-reactivity or cross-protection between the two serotypes in a guinea pig model of infection. However, partial cross-reactivity and cross-protection were reported in humans immunized with a SF2a lattice-type conjugate vaccine candidate comprising the chemically detoxified lipopolysaccharide (LPS) attached to recombinant Pseudomonas aeruginosa Exoprotein A (rEPA). Objectives This study aimed at deciphering the possible cross-reactivity with heterologous SF6 strains of antibodies induced in humans by SF2a-TT15, a sun-type SF2a conjugate vaccine candidate featuring a non- O -acetylated synthetic oligosaccharide (OS) as surrogate of the detoxified LPS. Special focus was on the impact of the O-SP non-stoichiometric O -acetylation on cross-reactivity. Methods Serum IgG antibody titers to LPSs from SF6 strains harboring different degrees of O-SP O -acetylation, and from Escherichia coli O147 (EC147) which shares an identical but non- O -acetylated O-SP with SF6, were measured by ELISA in 63 serum samples of volunteers receiving 2 µg and 10 µg OS doses of SF2a-TT15 or placebo in the frame of a phase I clinical study. Antibody in-lymphocyte-supernatants (ALS), avidity, and serum bactericidal activity (SBA) were measured in a subset of volunteers. Results SF2a-TT15 induced cross-reacting IgG antibodies to all SF6 LPSs and EC147 LPS. A ≥4-fold rise in anti-SF6 IgG titers was more frequent with the 10 µg dose than with 2 µg (50% vs 22%, p=0.045). Cross-reactivity rate was higher with the low O -acetylated SF6 O-SP than with the high O -acetylated one (50% versus 21%, p<0.05). Anti-SF6 responses correlated with homologous anti-SF2a LPS responses. Similar cross-reactivity was detected in ALS samples at day 7 after vaccination. Cross-reacting antibodies were partially functional against the heterologous SF6 parental strains, as shown by bactericidal activity and increased avidity. Conclusions SF2a-TT15 induces stronger SF6 cross-reactive IgG responses than the previously tested detoxified O -acetylated SF2a LPS–rEPA conjugate. While both serotypes are included in most multivalent Shigella vaccine candidates, cross-reactivity and cross-protection between SF2a and SF6 could enhance the immunogenicity and efficacy of a Shigella multivalent vaccine candidate, particularly in infants in low- and middle-income countries, the primary target population for a Shigella vaccine.