Evaluation of the Safety, Tolerability, and Immunogenicity of an Oral, Inactivated Whole-Cell Shigella flexneri 2a Vaccine in Healthy Adult Subjects.

Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6 ± 0.8 × 10(8), × 10(9), × 10(10), and × 10(11)vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples. Cytokines were measured in the serum. Sf2aWC was well tolerated and generally safe at all four dose levels. The vaccine resulted in a dose-dependent immune response. At the highest dose, the vaccine induced robust responses to lipopolysaccharide (LPS) in both serum and ALS samples. The highest magnitude and frequency of responses occurred after the first dose in almost all samples but was delayed for IgG in serum. Fifty percent of the vaccinees had a >4-fold increase in anti-LPS fecal antibody titers. Responses to invasion plasmid antigens (Ipa) were low. The levels of interleukin-17 (IL-17), IL-2, gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10 were increased, and IL-8 was decreased immediately after first dose, but these changes were very transient. This phase I trial demonstrated that the Sf2aWC vaccine, a relatively simple vaccine concept, was safe and immunogenic. The vaccine elicited immune responses which were comparable to those induced by a live, attenuated Shigella vaccine that was protective in prior human challenge studies.