Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously

Abstract

Transcutaneous immunization (TCI) is a new method for vaccine delivery that has been shown to induce immunity relevant to enteric disease vaccines. We evaluated the clinical safety and immunogenicity of a recombinant subunit vaccine against enterotoxigenic Escherichia coli (ETEC) delivered by TCI. Adult volunteers received patches containing the recombinant ETEC colonization factor CS6, either with heat-labile enterotoxin (LT) or patches containing CS6 alone. The vaccine was administered at 0, 1, and 3 months, and serum antibodies and antibody-secreting cells (ASCs) were assessed. Among the 26 volunteers that completed the trial, there were no responses to CS6 in the absence of LT. In the groups receiving both CS6 and LT, 68 and 53% were found to have serum anti-CS6 immunoglobulin G (IgG) and IgA, respectively; 37 and 42% had IgG and IgA anti-CS6 ASCs. All of the volunteers receiving LT had anti-LT IgG, and 90% had serum anti-LT IgA; 79 and 37% had anti-LT IgG and IgA ASCs. Delayed-type hypersensitivity (DTH), suggesting T-cell responses, was seen in 14 of 19 volunteers receiving LT and CS6; no DTH was seen in subjects receiving CS6 alone. This study demonstrated that protein antigens delivered by a simple patch could induce significant systemic immune responses but only in the presence of an adjuvant such as LT. The data suggest that an ETEC vaccine for travelers delivered by a patch may be a viable approach worthy of further evaluation.

FIG. 1.

Individual IgG and IgA peak fold rise in antibody titer to LT (A and B) and CS6 (C and D) among volunteers immunized with adjuvant combined with antigen (LT + CS6) or with antigen alone (CS6). The transverse bar represents the median peak fold rise in antibody titer.

FIG. 2.

Kinetics of the anti-LT (A and B) and anti-CS6 (C and D) IgA and IgG antibody responses among volunteers immunized and boosted (arrows) using the transcutaneous route. The circles indicate the geometric mean titer by the day after the first immunization; the bars denote the corresponding 95% confidence intervals (CI). ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001; NS, not statistically significant according to Wilcoxon signed rank test, comparing antibody titer responses between boosting immunizations.

FIG. 3.

Individual peak number of anti-LT (A and B) and anti-CS6 (C and D) ASCs per 10⁶ PBMC among responders to the immunization with adjuvant combined with antigen (LT + CS6), by the immunization after which the peak value was attained.