TY - JOUR
T1 - A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G
AU - Riddle, Mark S.
AU - Maciel, Milton
AU - Porter, Chad K.
AU - Poole, Steven T.
AU - Gutierrez, Ramiro L.
AU - Gormley, Robert
AU - Laird, Renee M.
AU - Sebeny, Peter J.
AU - Dori, Kathleen E.
AU - Greenleaf, Melissa E.
AU - Hoq, Fahmida
AU - Turiansky, George W.
AU - Jarell, Abel
AU - Hawk, Douglas
AU - Tribble, David
AU - Savarino, Stephen J.
N1 - Funding Information:
The authors are in debt to Ms. Glomil Corbin, Mrs. Dianna Zhang, Mr. William Hulsey and Mr. Ravi Dinesh for their excellent technical support. This study was approved by the ethical review committees of the Naval Medical Research Center, Silver Spring, MD (NMRC.2011.0004, WRAIR 1804, HSRRB Log No. A-16682) in compliance with all Federal regulations governing the protection of human volunteers and registered on ClinicalTrials.gov (NCT01382095 and NCT01644565). The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. Authors are military service members (or employees of the U.S. Government). This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. This study was conducted under support of Military Infectious Disease Research Program. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Publisher Copyright:
© 2020
PY - 2020/10/21
Y1 - 2020/10/21
N2 - Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among travelers and pediatric populations worldwide. The tip-localized adhesin of colonization factor antigen (CFA)/I fimbriae was engineered as a donor strand complemented variant (dscCfaE) and delivered via transcutaneous immunization. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. A series of open-label dose-escalating phase 1 studies evaluated a 3-dose (days 0, 21, 42) regimen via a transcutaneous skin patch. A total of forty-six subjects were enrolled into one of four vaccine dose levels (10, 50, 250, or 1250 µg) co-administered with single-mutant heat-labile enterotoxin (LTR(192G)). At the 50 µg dose level, ten subjects received the dscCfaE vaccine without LT(R192G). The vaccine was well tolerated with mild local vaccine site reactions characterized by an erythematous papular rash and pruritus, which were less frequent and reactive in the group not receiving LT(R192G). The frequency of responses to dscCfaE were moderate, whereas anti-toxin responses (serum IgA/IgG) ranged from 75 to 100% across groups that received LT(R192G). Antigen-specific antibody-secreting cell responses were elicited at all dose levels, but were generally low. Follow-on studies will optimize construct and route of delivery and assess efficacy in an ETEC challenge study.
AB - Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among travelers and pediatric populations worldwide. The tip-localized adhesin of colonization factor antigen (CFA)/I fimbriae was engineered as a donor strand complemented variant (dscCfaE) and delivered via transcutaneous immunization. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. A series of open-label dose-escalating phase 1 studies evaluated a 3-dose (days 0, 21, 42) regimen via a transcutaneous skin patch. A total of forty-six subjects were enrolled into one of four vaccine dose levels (10, 50, 250, or 1250 µg) co-administered with single-mutant heat-labile enterotoxin (LTR(192G)). At the 50 µg dose level, ten subjects received the dscCfaE vaccine without LT(R192G). The vaccine was well tolerated with mild local vaccine site reactions characterized by an erythematous papular rash and pruritus, which were less frequent and reactive in the group not receiving LT(R192G). The frequency of responses to dscCfaE were moderate, whereas anti-toxin responses (serum IgA/IgG) ranged from 75 to 100% across groups that received LT(R192G). Antigen-specific antibody-secreting cell responses were elicited at all dose levels, but were generally low. Follow-on studies will optimize construct and route of delivery and assess efficacy in an ETEC challenge study.
KW - Enterotoxigenic E. coli
KW - Immunogenicity
KW - LT(R192G)
KW - Safety
KW - Transcutaneous vaccine
UR - http://www.scopus.com/inward/record.url?scp=85091508115&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2020.09.025
DO - 10.1016/j.vaccine.2020.09.025
M3 - Article
C2 - 32978003
AN - SCOPUS:85091508115
SN - 0264-410X
VL - 38
SP - 7040
EP - 7048
JO - Vaccine
JF - Vaccine
IS - 45
ER -