Natural clostridioides difficile toxin immunization in colonized infants

Larry K. Kociolek; Robyn O. Espinosa; Dale N. Gerding; Alan R. Hauser; Egon A. Ozer; Maria Budz; Aakash Balaji; Xinhua Chen; Robert R. Tanz; Nazli Yalcinkaya; Margaret E. Conner; Tor Savidge; Ciaran P. Kelly

doi:10.1093/cid/ciz582

Natural clostridioides difficile toxin immunization in colonized infants

Larry K. Kociolek^*, Robyn O. Espinosa, Dale N. Gerding, Alan R. Hauser, Egon A. Ozer, Maria Budz, Aakash Balaji, Xinhua Chen, Robert R. Tanz, Nazli Yalcinkaya, Margaret E. Conner, Tor Savidge, Ciaran P. Kelly

^*Corresponding author for this work

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

29 Scopus citations

Abstract

Background. Clostridioides (Clostridium) difficile colonization is common among infants. Serological sequelae of infant C. difficile colonization are poorly understood. Methods. In this prospective cohort study of healthy infants, stools serially collected between ages 1-2 and 9-12 months were tested for non-toxigenic and toxigenic C. difficile (TCD). Cultured isolates underwent whole-genome sequencing. Serum collected at 9-12 months underwent measurement of IgA, IgG, and IgM against TCD toxins A and B and neutralizing antibody (NAb) titers against toxin B. For comparison, antitoxin IgG and NAb were measured in cord blood from 50 mothers unrelated to study infants. Results. Among 32 infants, 16 (50%) were colonized with TCD; 12 were first colonized >1 month before serology measurements. A variety of sequence types were identified, and there was evidence of putative in-home (enrolled siblings) and outpatient clinic transmission. Infants first colonized with TCD >1 month prior had significantly greater serum antitoxin IgA and IgG against toxins A (P =.02 for both) and B (P =.009 and.008, respectively) compared with non-TCD-colonized infants, and greater IgG compared with unrelated cord blood (P =.005). Five of 12 (42%) colonized infants had detectable NAb titers compared with zero non-TCD-colonized infants (P =.02). Breastfeeding was not associated with differences in serological measurements. Conclusions. TCD colonization is associated with a humoral immune response against toxins A and B, with evidence of toxin B neutralization in vitro. The extent and duration of protection against CDI later in life afforded by natural C. difficile immunization events require further investigation.

Original language	English (US)
Pages (from-to)	2095-2102
Number of pages	8
Journal	Clinical Infectious Diseases
Volume	70
Issue number	10
DOIs	https://doi.org/10.1093/cid/ciz582
State	Published - May 6 2020

Funding

Financial support. This work was supported by grants from Lurie Children’s Hospital (Pediatric Physician-Scientist Research Career Development Award to L. K. K.), the Gerber Foundation (Novice Researcher Award to L. K. K.), the American Cancer Society (grant number MRSG-13-220-01 to E. A. O.), the National Institute of Allergy and Infectious Diseases (grant numbers K23 AI123525 to L. K. K., K24 AI104831 to A. R. H., U01 AI24290 to T. S. and M. E. C., and R01 AI116596, U19 AI109776, and R01 AI132711 to C. P. K.), and the National Institute of Diabetes and Digestive and Kidney Diseases (grant number P30 DK56338 to T. S.) at the National Institutes of Health. Research reported in this publication was supported, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant number UL1TR001422.

Keywords

C. difficile
Immunity
Pediatric
Prevention
Toxin

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

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@article{379a0e8b4ee34fe38c6584805c26aea1,

title = "Natural clostridioides difficile toxin immunization in colonized infants",

abstract = "Background. Clostridioides (Clostridium) difficile colonization is common among infants. Serological sequelae of infant C. difficile colonization are poorly understood. Methods. In this prospective cohort study of healthy infants, stools serially collected between ages 1-2 and 9-12 months were tested for non-toxigenic and toxigenic C. difficile (TCD). Cultured isolates underwent whole-genome sequencing. Serum collected at 9-12 months underwent measurement of IgA, IgG, and IgM against TCD toxins A and B and neutralizing antibody (NAb) titers against toxin B. For comparison, antitoxin IgG and NAb were measured in cord blood from 50 mothers unrelated to study infants. Results. Among 32 infants, 16 (50%) were colonized with TCD; 12 were first colonized >1 month before serology measurements. A variety of sequence types were identified, and there was evidence of putative in-home (enrolled siblings) and outpatient clinic transmission. Infants first colonized with TCD >1 month prior had significantly greater serum antitoxin IgA and IgG against toxins A (P =.02 for both) and B (P =.009 and.008, respectively) compared with non-TCD-colonized infants, and greater IgG compared with unrelated cord blood (P =.005). Five of 12 (42%) colonized infants had detectable NAb titers compared with zero non-TCD-colonized infants (P =.02). Breastfeeding was not associated with differences in serological measurements. Conclusions. TCD colonization is associated with a humoral immune response against toxins A and B, with evidence of toxin B neutralization in vitro. The extent and duration of protection against CDI later in life afforded by natural C. difficile immunization events require further investigation.",

keywords = "C. difficile, Immunity, Pediatric, Prevention, Toxin",

author = "Kociolek, {Larry K.} and Espinosa, {Robyn O.} and Gerding, {Dale N.} and Hauser, {Alan R.} and Ozer, {Egon A.} and Maria Budz and Aakash Balaji and Xinhua Chen and Tanz, {Robert R.} and Nazli Yalcinkaya and Conner, {Margaret E.} and Tor Savidge and Kelly, {Ciaran P.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].",

year = "2020",

month = may,

day = "6",

doi = "10.1093/cid/ciz582",

language = "English (US)",

volume = "70",

pages = "2095--2102",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "10",

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TY - JOUR

T1 - Natural clostridioides difficile toxin immunization in colonized infants

AU - Kociolek, Larry K.

AU - Espinosa, Robyn O.

AU - Gerding, Dale N.

AU - Hauser, Alan R.

AU - Ozer, Egon A.

AU - Budz, Maria

AU - Balaji, Aakash

AU - Chen, Xinhua

AU - Tanz, Robert R.

AU - Yalcinkaya, Nazli

AU - Conner, Margaret E.

AU - Savidge, Tor

AU - Kelly, Ciaran P.

PY - 2020/5/6

Y1 - 2020/5/6

N2 - Background. Clostridioides (Clostridium) difficile colonization is common among infants. Serological sequelae of infant C. difficile colonization are poorly understood. Methods. In this prospective cohort study of healthy infants, stools serially collected between ages 1-2 and 9-12 months were tested for non-toxigenic and toxigenic C. difficile (TCD). Cultured isolates underwent whole-genome sequencing. Serum collected at 9-12 months underwent measurement of IgA, IgG, and IgM against TCD toxins A and B and neutralizing antibody (NAb) titers against toxin B. For comparison, antitoxin IgG and NAb were measured in cord blood from 50 mothers unrelated to study infants. Results. Among 32 infants, 16 (50%) were colonized with TCD; 12 were first colonized >1 month before serology measurements. A variety of sequence types were identified, and there was evidence of putative in-home (enrolled siblings) and outpatient clinic transmission. Infants first colonized with TCD >1 month prior had significantly greater serum antitoxin IgA and IgG against toxins A (P =.02 for both) and B (P =.009 and.008, respectively) compared with non-TCD-colonized infants, and greater IgG compared with unrelated cord blood (P =.005). Five of 12 (42%) colonized infants had detectable NAb titers compared with zero non-TCD-colonized infants (P =.02). Breastfeeding was not associated with differences in serological measurements. Conclusions. TCD colonization is associated with a humoral immune response against toxins A and B, with evidence of toxin B neutralization in vitro. The extent and duration of protection against CDI later in life afforded by natural C. difficile immunization events require further investigation.

AB - Background. Clostridioides (Clostridium) difficile colonization is common among infants. Serological sequelae of infant C. difficile colonization are poorly understood. Methods. In this prospective cohort study of healthy infants, stools serially collected between ages 1-2 and 9-12 months were tested for non-toxigenic and toxigenic C. difficile (TCD). Cultured isolates underwent whole-genome sequencing. Serum collected at 9-12 months underwent measurement of IgA, IgG, and IgM against TCD toxins A and B and neutralizing antibody (NAb) titers against toxin B. For comparison, antitoxin IgG and NAb were measured in cord blood from 50 mothers unrelated to study infants. Results. Among 32 infants, 16 (50%) were colonized with TCD; 12 were first colonized >1 month before serology measurements. A variety of sequence types were identified, and there was evidence of putative in-home (enrolled siblings) and outpatient clinic transmission. Infants first colonized with TCD >1 month prior had significantly greater serum antitoxin IgA and IgG against toxins A (P =.02 for both) and B (P =.009 and.008, respectively) compared with non-TCD-colonized infants, and greater IgG compared with unrelated cord blood (P =.005). Five of 12 (42%) colonized infants had detectable NAb titers compared with zero non-TCD-colonized infants (P =.02). Breastfeeding was not associated with differences in serological measurements. Conclusions. TCD colonization is associated with a humoral immune response against toxins A and B, with evidence of toxin B neutralization in vitro. The extent and duration of protection against CDI later in life afforded by natural C. difficile immunization events require further investigation.

KW - C. difficile

KW - Immunity

KW - Pediatric

KW - Prevention

KW - Toxin

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U2 - 10.1093/cid/ciz582

DO - 10.1093/cid/ciz582

M3 - Article

C2 - 31253983

AN - SCOPUS:85084272195

SN - 1058-4838

VL - 70

SP - 2095

EP - 2102

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 10

ER -

Natural clostridioides difficile toxin immunization in colonized infants

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