TY - JOUR
T1 - Evaluation of the immunogenicity and protective efficacy of a recombinant CS6-based ETEC vaccine in an Aotus nancymaae CS6 + ETEC challenge model
AU - Ramakrishnan, A.
AU - Joseph, S. S.
AU - Reynolds, N. D.
AU - Poncet, D.
AU - Maciel, M.
AU - Nunez, G.
AU - Espinoza, N.
AU - Nieto, M.
AU - Castillo, R.
AU - Royal, J. M.
AU - Poole, S.
AU - McVeigh, A.
AU - Rollenhagen, J. E.
AU - Heinrichs, J.
AU - Prouty, M. G.
AU - Simons, M. P.
AU - Renauld-Mongénie, G.
AU - Savarino, S. J.
N1 - Funding Information:
The authors wish to thank the Walter Reed Army Institute of Research for the provision of recombinant CS6. We thank Elise De Castro and Xavier Louis for their excellent technical assistance in the development of an LT seroneutralization assay and the CS6 Flow Cytometry assay, respectively. This research was supported by U.S. Army Military Infectious Diseases Research Program Work Unit Number U.S. Navy WUN A1009, Henry M. Jackson foundation for the Advancement of Military Medicine, and Sanofi Pasteur (NCRADA-NMR-09-3183). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. the Department of the Navy, Department of Defense, nor the U.S. Government. S.J.S. N.D.R. J.M.R. M.P.S. and M.G.P. served as military service members over the course of this work, which was prepared as part of their official duties. Title 17 USC. §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. D.P. J.H. and G.R-M. are employees of Sanofi Pasteur. S.J.S. was an employee of the U.S. Navy and served as the Principal Investigator for NMRC and USUHS at the time of the study and is now an employee of Sanofi Pasteur. He was inventor on an issued patent held by the US Navy for adhesins as immunogens against enterotoxigenic Escherichia coli, and in the past received royalty through a licensing agreement between the U.S. Navy and Sanofi Pasteur. All other authors declare that there are no financial, institutional, or other relationship that might lead to bias or a conflict of interest.
Funding Information:
The authors wish to thank the Walter Reed Army Institute of Research for the provision of recombinant CS6. We thank Elise De Castro and Xavier Louis for their excellent technical assistance in the development of an LT seroneutralization assay and the CS6 Flow Cytometry assay, respectively. This research was supported by U.S. Army Military Infectious Diseases Research Program Work Unit Number U.S. Navy WUN A1009, Henry M. Jackson foundation for the Advancement of Military Medicine, and Sanofi Pasteur (NCRADA-NMR-09-3183). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Henry M. Jackson Foundation for the Advancement of Military Medicine , Inc., the Department of the Navy, Department of Defense, nor the U.S. Government. S.J.S. N.D.R., J.M.R., M.P.S. and M.G.P. served as military service members over the course of this work, which was prepared as part of their official duties. Title 17 USC. §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. D.P., J.H. and G.R-M. are employees of Sanofi Pasteur. S.J.S. was an employee of the U.S. Navy and served as the Principal Investigator for NMRC and USUHS at the time of the study and is now an employee of Sanofi Pasteur. He was inventor on an issued patent held by the US Navy for adhesins as immunogens against enterotoxigenic Escherichia coli, and in the past received royalty through a licensing agreement between the U.S. Navy and Sanofi Pasteur. All other authors declare that there are no financial, institutional, or other relationship that might lead to bias or a conflict of interest.
Publisher Copyright:
© 2020
PY - 2021/1/15
Y1 - 2021/1/15
N2 - Colonization factors or Coli surface antigens (CFs or CS) are important virulence factors of Enterotoxigenic E. coli (ETEC) that mediate intestinal colonization and accordingly are targets of vaccine development efforts. CS6 is a highly prevalent CF associated with symptomatic ETEC infection both in endemic populations and amongst travelers. In this study, we used an Aotus nancymaae non-human primate ETEC challenge model with a CS6 + ETEC strain, B7A, to test the immunogenicity and protective efficacy (PE) of a recombinant CS6-based subunit vaccine. Specifically, we determined the ability of dscCssBA, the donor strand complemented recombinant stabilized fusion of the two subunits of the CS6 fimbriae, CssA and CssB, to elicit protection against CS6 + ETEC mediated diarrhea when given intradermally (ID) with the genetically attenuated double mutant heat-labile enterotoxin LT(R192G/L211A) (dmLT). ID vaccination with dscCssBA + dmLT induced strong serum antibody responses against CS6 and LT. Importantly, vaccination with dscCssBA + dmLT resulted in no observed diarrheal disease (PE = 100%, p = 0.03) following B7A challenge as compared to PBS immunized animals, with an attack rate of 62.5%. These data demonstrate the potential role that CS6 may play in ETEC infection and that recombinant dscCssBA antigen can provide protection against challenge with the homologous CS6 + ETEC strain, B7A, in the Aotus nancymaae diarrheal challenge model. Combined, these data indicate that CS6, and more specifically, a recombinant engineered derivative should be considered for further clinical development.
AB - Colonization factors or Coli surface antigens (CFs or CS) are important virulence factors of Enterotoxigenic E. coli (ETEC) that mediate intestinal colonization and accordingly are targets of vaccine development efforts. CS6 is a highly prevalent CF associated with symptomatic ETEC infection both in endemic populations and amongst travelers. In this study, we used an Aotus nancymaae non-human primate ETEC challenge model with a CS6 + ETEC strain, B7A, to test the immunogenicity and protective efficacy (PE) of a recombinant CS6-based subunit vaccine. Specifically, we determined the ability of dscCssBA, the donor strand complemented recombinant stabilized fusion of the two subunits of the CS6 fimbriae, CssA and CssB, to elicit protection against CS6 + ETEC mediated diarrhea when given intradermally (ID) with the genetically attenuated double mutant heat-labile enterotoxin LT(R192G/L211A) (dmLT). ID vaccination with dscCssBA + dmLT induced strong serum antibody responses against CS6 and LT. Importantly, vaccination with dscCssBA + dmLT resulted in no observed diarrheal disease (PE = 100%, p = 0.03) following B7A challenge as compared to PBS immunized animals, with an attack rate of 62.5%. These data demonstrate the potential role that CS6 may play in ETEC infection and that recombinant dscCssBA antigen can provide protection against challenge with the homologous CS6 + ETEC strain, B7A, in the Aotus nancymaae diarrheal challenge model. Combined, these data indicate that CS6, and more specifically, a recombinant engineered derivative should be considered for further clinical development.
KW - CS6
KW - ETEC
KW - Enterotoxigenic Escherichia coli
KW - Intradermal
KW - Nonhuman primates
KW - Vaccine
UR - http://www.scopus.com/inward/record.url?scp=85098053196&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2020.12.034
DO - 10.1016/j.vaccine.2020.12.034
M3 - Article
C2 - 33357957
AN - SCOPUS:85098053196
SN - 0264-410X
VL - 39
SP - 487
EP - 494
JO - Vaccine
JF - Vaccine
IS - 3
ER -