A replicating single-cycle adenovirus vaccine effective against clostridium difficile

William E. Matchett; Stephanie Anguiano-Zarate; Goda Baddage Rakitha Malewana; Haley Mudrick; Melissa Weldy; Clayton Evert; Alexander Khoruts; Michael Sadowsky; Michael A. Barry

doi:10.3390/vaccines8030470

A replicating single-cycle adenovirus vaccine effective against clostridium difficile

William E. Matchett, Stephanie Anguiano-Zarate, Goda Baddage Rakitha Malewana, Haley Mudrick, Melissa Weldy, Clayton Evert, Alexander Khoruts, Michael Sadowsky, Michael A. Barry

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

Original language	English (US)
Article number	470
Pages (from-to)	1-15
Number of pages	15
Journal	Vaccines
Volume	8
Issue number	3
DOIs	https://doi.org/10.3390/vaccines8030470
State	Published - 2020

Bibliographical note

Funding Information:
Funding: This work was supported by the Discovery Translation Fund of the Mayo Clinic and the Walter & Lucille Rubin Fund in Infectious Diseases Honoring Michael Camilleri, M.D. at the Mayo Clinic. This work was also funded in part by the Intramural Research Program, NIAID to A.M. S.S.A.Z., and this publication was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS, NIH). S.S.A.Z. was also supported by the Initiative for Maximizing Student Development (IMSD) at Mayo Clinic. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Contributions of M.W., C.E., A.K., M.J.S. were supported by the Department of Defense grant W81XWH-17-1-0636 Acknowledgments: We would like to thank Mary Barry, Jeff Rubin, and Brady Zell for their invaluable technical assistance. We would like to thank the Mayo Clinic Toxicology and Pharmacology Laboratory that includes Michael Steele, Alysha Newsom, Nate Jenks, and Kah Whye Peng for their excellent and invaluable assistance in performing the toxicology experiments. We would like thank Nigel Minton and Michelle Kelly for providing their scoring criteria for measuring infection severity in hamsters.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Adenovirus
Animal models
Clostridium difficile
Single-cycle
Vaccine

PubMed: MeSH publication types

Journal Article

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "A replicating single-cycle adenovirus vaccine effective against clostridium difficile",

abstract = "Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile{\textquoteright}s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.",

keywords = "Adenovirus, Animal models, Clostridium difficile, Single-cycle, Vaccine",

author = "Matchett, {William E.} and Stephanie Anguiano-Zarate and Malewana, {Goda Baddage Rakitha} and Haley Mudrick and Melissa Weldy and Clayton Evert and Alexander Khoruts and Michael Sadowsky and Barry, {Michael A.}",

note = "Funding Information: Funding: This work was supported by the Discovery Translation Fund of the Mayo Clinic and the Walter & Lucille Rubin Fund in Infectious Diseases Honoring Michael Camilleri, M.D. at the Mayo Clinic. This work was also funded in part by the Intramural Research Program, NIAID to A.M. S.S.A.Z., and this publication was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS, NIH). S.S.A.Z. was also supported by the Initiative for Maximizing Student Development (IMSD) at Mayo Clinic. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Contributions of M.W., C.E., A.K., M.J.S. were supported by the Department of Defense grant W81XWH-17-1-0636 Acknowledgments: We would like to thank Mary Barry, Jeff Rubin, and Brady Zell for their invaluable technical assistance. We would like to thank the Mayo Clinic Toxicology and Pharmacology Laboratory that includes Michael Steele, Alysha Newsom, Nate Jenks, and Kah Whye Peng for their excellent and invaluable assistance in performing the toxicology experiments. We would like thank Nigel Minton and Michelle Kelly for providing their scoring criteria for measuring infection severity in hamsters. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Matchett, William E.

AU - Anguiano-Zarate, Stephanie

AU - Malewana, Goda Baddage Rakitha

AU - Mudrick, Haley

AU - Weldy, Melissa

AU - Evert, Clayton

AU - Khoruts, Alexander

AU - Sadowsky, Michael

AU - Barry, Michael A.

N1 - Funding Information: Funding: This work was supported by the Discovery Translation Fund of the Mayo Clinic and the Walter & Lucille Rubin Fund in Infectious Diseases Honoring Michael Camilleri, M.D. at the Mayo Clinic. This work was also funded in part by the Intramural Research Program, NIAID to A.M. S.S.A.Z., and this publication was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS, NIH). S.S.A.Z. was also supported by the Initiative for Maximizing Student Development (IMSD) at Mayo Clinic. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Contributions of M.W., C.E., A.K., M.J.S. were supported by the Department of Defense grant W81XWH-17-1-0636 Acknowledgments: We would like to thank Mary Barry, Jeff Rubin, and Brady Zell for their invaluable technical assistance. We would like to thank the Mayo Clinic Toxicology and Pharmacology Laboratory that includes Michael Steele, Alysha Newsom, Nate Jenks, and Kah Whye Peng for their excellent and invaluable assistance in performing the toxicology experiments. We would like thank Nigel Minton and Michelle Kelly for providing their scoring criteria for measuring infection severity in hamsters. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020

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N2 - Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

AB - Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

KW - Adenovirus

KW - Animal models

KW - Clostridium difficile

KW - Single-cycle

KW - Vaccine

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U2 - 10.3390/vaccines8030470

DO - 10.3390/vaccines8030470

M3 - Article

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AN - SCOPUS:85090809854

SN - 2076-393X

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JF - Vaccines

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ER -

A replicating single-cycle adenovirus vaccine effective against clostridium difficile

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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