TY - JOUR
T1 - Shigella-Specific Immune Profiles Induced after Parenteral Immunization or Oral Challenge with Either Shigella flexneri 2a or Shigella sonnei
AU - Clarkson, Kristen A.
AU - Clarkson, Kristen A.
AU - Talaat, Kawsar R.
AU - Frenck, Robert W.
AU - Alaimo, Cristina
AU - Martin, Patricia
AU - Bourgeois, A. Louis
AU - Kaminski, Robert W.
N1 - Funding Information:
Funding for the Phase 2b bioconjugate vaccine efficacy trial was provided by the Wellcome Trust. Funding for the S. sonnei 53G CHIM was provided by the Military Infectious Disease Research Program under award no. D0437_15_NM and contracted to the Cincinnati Children’s Hospital Medical Center from the Natick Contracting Division (W911QY-16-2-0002). The study was also funded by a Collaborative Research and Development Agreement (CRADA) with PATH, the Walter Reed Army Institute of Research, and the Cincinnati Children’s Hospital Medical Center (ORTA no. 4516). Partial funding for this CRADA was provided by the Bill & Melinda Gates Foundation (OPP1112376).
Funding Information:
We acknowledge K. Ross Turbyfill for providing the antigens utilized in the immunoassays and Akamol E. Suvarnapunya for critical reading of the manuscript. K. A. Clarkson, C. K. Porter, and R. W. Kaminski are employees of the U.S. Government. This work was prepared as part of their official duties. Material has been reviewed by the publication. The opinions or assertions contained herein are the private views of the of the Army, Department of the Navy, or the Department of Defense, nor the U.S. Government. Funding for the Phase 2b bioconjugate vaccine efficacy trial was provided by the Wellcome Trust. Funding for the S. sonnei 53G CHIM was provided by the Military Infectious Disease Research Program under award no. D0437_15_NM and contracted to the Cincinnati Children?s Hospital Medical Center from the Natick Contracting Division (W911QY-16-2-0002). The study was also funded by a Collaborative Research and Development Agreement (CRADA) with PATH, the Walter Reed Army Institute of Research, and the Cincinnati Children?s Hospital Medical Center (ORTA no. 4516). Partial funding for this CRADA was provided by the Bill & Melinda Gates Foundation (OPP1112376). None of the authors has a conflict of interest for any of the materials presented in the manuscript.
Publisher Copyright:
© May Apply
PY - 2021/8
Y1 - 2021/8
N2 - Shigella spp. are a leading cause of diarrhea-associated global morbidity and mortality. Development and widespread implementation of an efficacious vaccine remain the best option to reduce Shigella-specific morbidity. Unfortunately, the lack of a well-defined correlate of protection for shigellosis continues to hinder development efforts. Shigella controlled human infection models (CHIM) are often used in the early stages of vaccine development to provide preliminary estimates of vaccine efficacy; however, CHIMs also provide the opportunity to conduct in-depth immune response characterizations pre and postvaccination or pre and postinfection. In the current study, principal-component analyses were used to examine immune response data from two recent Shigella CHIMs in order to characterize immune response profiles associated with parenteral immunization, oral challenge with Shigella flexneri 2a, or oral challenge with Shigella sonnei. Although immunization induced an immune profile characterized by robust systemic antibody responses, it also included mucosal responses. Interestingly, oral challenge with S. flexneri 2a induced a distinctively different profile compared to S. sonnei, characterized by a relatively balanced systemic and mucosal response. In contrast, S. sonnei induced robust increases in mucosal antibodies with no differences in systemic responses across shigellosis outcomes postchallenge. Furthermore, S. flexneri 2a challenge induced significantly higher levels of intestinal inflammation compared to S. sonnei, suggesting that both serotypes may also differ in how they trigger innate immunity. These findings could have important Shigella vaccine development as protective immune mechanisms shigellosis, prior studies have demonstrated that Shigella infection provides protection against reinfection in a serotype-specific manner. Therefore, it is likely that subjects with moderate to severe disease post-oral challenge would be protected from a homologous rechallenge, and investigating immune responses in these subjects may help identify immune markers associated with the development of protective immunity. This is the first study to describe distinct innate and adaptive immune profiles post-oral challenge with two different Shigella serotypes. Analyses conducted here provide essential insights into the potential of different immune mechanisms required to elicit protective immunity, depending on the serotype.
AB - Shigella spp. are a leading cause of diarrhea-associated global morbidity and mortality. Development and widespread implementation of an efficacious vaccine remain the best option to reduce Shigella-specific morbidity. Unfortunately, the lack of a well-defined correlate of protection for shigellosis continues to hinder development efforts. Shigella controlled human infection models (CHIM) are often used in the early stages of vaccine development to provide preliminary estimates of vaccine efficacy; however, CHIMs also provide the opportunity to conduct in-depth immune response characterizations pre and postvaccination or pre and postinfection. In the current study, principal-component analyses were used to examine immune response data from two recent Shigella CHIMs in order to characterize immune response profiles associated with parenteral immunization, oral challenge with Shigella flexneri 2a, or oral challenge with Shigella sonnei. Although immunization induced an immune profile characterized by robust systemic antibody responses, it also included mucosal responses. Interestingly, oral challenge with S. flexneri 2a induced a distinctively different profile compared to S. sonnei, characterized by a relatively balanced systemic and mucosal response. In contrast, S. sonnei induced robust increases in mucosal antibodies with no differences in systemic responses across shigellosis outcomes postchallenge. Furthermore, S. flexneri 2a challenge induced significantly higher levels of intestinal inflammation compared to S. sonnei, suggesting that both serotypes may also differ in how they trigger innate immunity. These findings could have important Shigella vaccine development as protective immune mechanisms shigellosis, prior studies have demonstrated that Shigella infection provides protection against reinfection in a serotype-specific manner. Therefore, it is likely that subjects with moderate to severe disease post-oral challenge would be protected from a homologous rechallenge, and investigating immune responses in these subjects may help identify immune markers associated with the development of protective immunity. This is the first study to describe distinct innate and adaptive immune profiles post-oral challenge with two different Shigella serotypes. Analyses conducted here provide essential insights into the potential of different immune mechanisms required to elicit protective immunity, depending on the serotype.
KW - Shigella
KW - antibody
KW - correlate of protection
KW - gut-homing responses
KW - human challenge
KW - immune profile
KW - immunogenicity
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U2 - 10.1128/mSphere.00122-21
DO - 10.1128/mSphere.00122-21
M3 - Article
C2 - 34259559
AN - SCOPUS:85115040305
SN - 2379-5042
VL - 6
SP - 1
EP - 19
JO - mSphere
JF - mSphere
IS - 4
ER -