A new human challenge model for testing heat-stable toxin-based vaccine candidates for enterotoxigenic Escherichia coli diarrhea - dose optimization, clinical outcomes, and CD4 + T cell responses
JournalPLoS Neglected Tropical Diseases
PublisherPublic Library of Science
MetadataShow full item record
AbstractEnterotoxigenic Escherichia coli (ETEC) are a common cause of diarrheal illness in young children and travelers. There is yet no licensed broadly protective vaccine against ETEC. One promising vaccine development strategy is to target strains expressing the heat-stable toxin (ST), particularly the human ST (STh), since infections with these strains are among the leading causes of diarrhea in children in low-and-middle income countries. A human challenge model based on an STh-only ETEC strain will be useful to evaluate the protective efficacy of new ST-based vaccine candidates. To develop this model, we experimentally infected 21 healthy adult volunteers with the epidemiologically relevant STh-only ETEC strain TW10722, identified a suitable dose, assessed safety, and characterized clinical outcomes and immune responses caused by the infection. Doses of 1×10(10) colony-forming units (CFU) of TW10722 gave a suitable attack risk of 67% for moderate or severe diarrhea and an overall diarrhea attack risk of 78%. Non-diarrheal symptoms were mostly mild or moderate, and there were no serious adverse events. During the first month after ingesting the challenge strain, we measured significant increases in both activated CD4+ T cells and levels of serum IgG and IgA antibodies targeting coli surface antigen 5 (CS5) and 6 (CS6), as well as the E. coli mucinase YghJ. The CS5-specific CD4+ T cell and antibody responses were still significantly elevated one year after experimental infection. In conclusion, we have developed a safe STh-only ETEC-based human challenge model which can be efficiently used in Phase 2B trials to evaluate the protective efficacy of new ST-based vaccine candidates. Copyright 2019 Sakkestad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
SponsorsThis work was partly supported by the Research Council of Norway through the Global Health and Vaccination Programme (GLOBVAC) (https://www.forskningsradet.no/en/), project number 234364. The project has received funding from the European Union?s Seventh Framework Programme (https://ec.europa.eu/research/fp7/index_en.cfm) for research, technological development and demonstration under Grant Agreement no 261472-STOPENTERICS. The project was also supported by funding from the Enteric Vaccine Initiative (EVI) (https://www.path.org/) for the R&D project titled ?Developing a safe STh-based vaccine for protection against ETEC diarrhoea?. The contribution by HSo and HSt was in part supported by the Centre for Intervention Science in Maternal and Child Health (CISMAC; project number 223269) (https://www.forskningsradet.no/en/), which is funded by the Research Council of Norway through its Centres of Excellence scheme and the University of Bergen (UiB), Norway. The contribution of STS was in part supported by a PhD grant from the University of Bergen, Norway (https://www.uib.no/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywordheat-stable toxin (ST)
Enterotoxigenic Escherichia coli
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85074873190&doi=10.1371%2fjournal.pntd.0007823&partnerID=40&md5=d58e7fc29fc59b3f4f385f80cca62263; http://hdl.handle.net/10713/11434
- Passive antibodies derived from intramuscularly immunized toxoid fusion 3xSTa<sub>N12S</sub>-dmLT protect against STa+ enterotoxigenic Escherichia coli (ETEC) diarrhea in a pig model.
- Authors: Nandre RM, Duan Q, Wang Y, Zhang W
- Issue date: 2017 Jan 23
- Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines.
- Authors: Harro C, Chakraborty S, Feller A, DeNearing B, Cage A, Ram M, Lundgren A, Svennerholm AM, Bourgeois AL, Walker RI, Sack DA
- Issue date: 2011 Oct
- Safety and immunogenicity of a single oral dose of recombinant double mutant heat-labile toxin derived from enterotoxigenic Escherichia coli.
- Authors: El-Kamary SS, Cohen MB, Bourgeois AL, Van De Verg L, Bauers N, Reymann M, Pasetti MF, Chen WH
- Issue date: 2013 Nov
- A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization.
- Authors: Bernstein DI, Pasetti MF, Brady R, Buskirk AD, Wahid R, Dickey M, Cohen M, Baughman H, El-Khorazaty J, Maier N, Sztein MB, Baqar S, Bourgeois AL
- Issue date: 2019 Jan 21
- A tripartite fusion, FaeG-FedF-LT(192)A2:B, of enterotoxigenic Escherichia coli (ETEC) elicits antibodies that neutralize cholera toxin, inhibit adherence of K88 (F4) and F18 fimbriae, and protect pigs against K88ac/heat-labile toxin infection.
- Authors: Ruan X, Liu M, Casey TA, Zhang W
- Issue date: 2011 Oct