Safety and Immunogenicity of a Prototype EnterotoxigenicEscherichia coliVaccine 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.

A synthetic HIV‐1 Tat protein breaches the skin barrier and elicits Tat‐neutralizing antibodies and cellular immunity

“…It is important to note that there were no any apparent signs of skin inflammation during or after immunization. This is consistent with published reports about the safety of this immunization procedure [19,20]. A control group of four mice was immunized subcutaneously with 10 lg sTat emulsified in IFA and boosted 2 weeks later with the same antigen formulation.…”

“…Transcutaneous immunization is based on the co-application of antigen with an ADPribosylating exotoxin, such as cholera toxin (CT) secreted by Vibrio cholerae [11], heat-labile enterotoxin of Escherichia coli (LT) [14,15] or mutants of LT [14,16,17] onto hydrated bare skin. Studies in mice have shown that transcutaneous immunization elicits systemic and mucosal immune responses to various types of antigens including proteins, peptides, glycoconjugate vaccines, viruses and plasmid DNA [18], and its potential was more recently shown in humans [19,20].…”

“…It is composed of 86-101 amino acid residues (depending on the isolate) encoded by two exons. The first 72 amino acid residues (encoded by the first exon) are organized into three functional domains: (i) an acidic N-terminal region (aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] that binds to cell surface CD26 and is thought to mediate immunosuppressive activity [3]; (ii) a cysteine-rich domain (aa [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] that mediates binding to chemokine receptors [4]; and (iii) the basic domain (aa 41-60). The latter domain is responsible for the internalization of extracellular Tat and its import into the nucleus and is also required for binding to short RNA transcripts containing the viral transactivation-responsive element (TAR) [5,6].…”

Transcutaneous Immunization with Cross-Reacting Material CRM 197 of Diphtheria Toxin Boosts Functional Antibody Levels in Mice Primed Parenterally with Adsorbed Diphtheria Toxoid Vaccine

“…These concerns are perhaps less relevant for skin delivery and are likely to be site and route specific due to the proximity of key neurological pathways to the site of antigen/adjuvant application at the nasal mucosa. The LT holotoxin is reportedly safe when used as an adjuvant on human skin (9,12). However, this toxin has been shown to cause some mild local side effects following TCI in humans (reviewed in reference 31), and partially or fully detoxified mutants of bacterial toxins, such as LTR72, may become adjuvants of choice for future human use-particularly when they are shown to be equally or more effective as fully active holotoxins.…”

Prevention and self-treatment of travelers' diarrhea

“…Subsequent studies with Egyptian children and adults (72), and with Bangladeshi children (132,133), have confirmed the vaccine's safety and immunogenicity in these settings where the disease is endemic, although the results of larger efficacy studies are pending. Other ETEC vaccines under development include recombinant ETEC CF CS6 in combination with LT, delivered transcutaneously by means of a topical patch (71); an oral liveattenuated vaccine (167); and a candidate vaccine consisting of CS6 encapsulated in biodegradable microspheres (96). All three of these candidates have been evaluated in phase 1 studies and have demonstrated promising safety and immunogenicity profiles.…”