Cellular and humoral immunity are synergistic in protection against types A and B Francisella tularensis

Abstract

Herein we report studies with a novel combination vaccine that, when administered to mice, conferred protection against highly virulent strains of Francisella tularensis by stimulating both arms of the immune system. Our earlier studies with Ft.LVS::wbtA, an O-polysaccharide (OPS)-negative mutant derived from the available live vaccine strain of F. tularensis (Ft.LVS), elucidated the role of antibodies to the OPS-a key virulence determinant-in protection against virulent type A organisms. However, when expressed on the organism, the OPS enhances virulence. In contrast, in purified form, the OPS is completely benign. We hypothesized that a novel combination vaccine containing both a component that induces humoral immunity and a component that induces cellular immunity to this intracellular microbe would have an enhanced protective capacity over either component alone and would be much safer than the LVS vaccine. Thus we developed a combination vaccine containing both OPS (supplied in an OPS-tetanus toxoid glycoconjugate) to induce a humoral antibody response and strain Ft.LVS::wbtA (which is markedly attenuated by its lack of OPS) to induce a cell-mediated protective response. This vaccine protected mice against otherwise-lethal intranasal and intradermal challenge with wildtype F. tularensis strains Schu S4 (type A) and FSC 108 (type B). These results represent a significant advance in our understanding of immunity to F. tularensis and provide important insight into the development of a safer vaccine effective against infections caused by clinical type A and B strains of F. tularensis.

Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

“…Similarly, studies with passively administered antibodies show that although antibodies elicited to Ft LVS protect against lethal challenge, antibodies elicited by immunization with the Oantigen-deficient strain, Ft LVS wbtA, do not (30,31). Furthermore, passively administered rabbit anti-Ft LVS antisera, but not antisera depleted of anti-O antibodies, protected mice against lethal challenge (31).…”

Correlates of Protection Induced by Vaccination

“…However, induction of cellular immunity in addition to antibody is necessary for maximum protection (161,165).…”

Host–pathogen interactions and immune evasion strategies in Francisella tularensis pathogenicity

“…However, serum transfer from mice immunized with LPS and boosted with F. tularensis LVS failed to protect naïve mice depleted of either CD4 + or CD8 + T-cells 108. A combination vaccine containing tetanus-toxin-conjugated O-polysaccharide (to generate an antibody response) and an LVS mutant lacking the O-polysaccharide (to generate a T-cell response) protected mice against intranasal and intradermal infection with the type A strain Schu S4 and the type B strain FSC 108 better than either vaccine component alone 109. Humoral immunity may also enhance the T-cell response.…”