Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study

ABSTRACT

Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.

KEYWORDS:

• Urinary tract infection
• vaccine
• FimH
• TLR4 agonist
• phase 1

Acknowledgments

We thank Ginger Constantine, MD for medical monitoring; Derry Ridgeway, MD and Ginger Constantine, MD for their contributions on the safety review committee; Innovative Analytics (Kalamazoo, MI) for data collection and storage and preparation of the data tables and statistical analysis; Karen Goldenthal, MD for assisting with development of the study protocol; William Egan, PhD for contributions to analytical development; Tatyana Touzova for contributions to analytical development and quality assurance; Thomas M. Hooton, MD for advice and expertise pertaining to patients with recurrent UTI; Jerry Pinkner for guidance and expertise with FimCH manufacturing; and Scott Hultgren, PhD for advice, expertise and insights pertaining to the virulence mechanisms involved with recurrent UTI.

Disclosure of potential conflicts of interest

This study was funded by Sequoia Sciences. All authors were employees, contractors, consultants, or shareholders of Sequoia Sciences.

Contributors

GRE and HH conceived the phase 1 study design, development of the study protocol, and data analysis and interpretation. LR contributed with the development of the study protocol and execution of the study. AMS, ED, KGC, ASL, NS, and JP were clinical investigators and designees and contributed to subject recruitment, study procedures, and data acquisitions. LR and HH provided study medical and safety oversight. SMM provided advice and expertise. GRE and CMS wrote the manuscript.

Abbreviations

UTI

=

urinary tract infections

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This study was funded by Sequoia Sciences. Employees of Sequoia Sciences are named as authors on this manuscript and contributed to the design and execution of the phase 1 study, and interpretation of data. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.