Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment

• Published in: mSphere 2020-05, Vol.5 (3)
• Main Authors: Shen, Judong, Mehrotra, Devan V, Dorr, Mary Beth, Zeng, Zhen, Li, Junhua, Xu, Xun, Nickle, David, Holzinger, Emily R, Chhibber, Aparna, Wilcox, Mark H, Blanchard, Rebecca L, Shaw, Peter M
• Format: Article
• Language: English
• Subjects: Age; Alleles; Antibiotics; Antigens; Chromosome 6; Clinical trials; Clostridium difficile; Confidence intervals; DQA1 protein; Drb1 protein; Gene expression; Genetic diversity; Genetic variability; Genome-wide association studies; Genomes; Genotype & phenotype; Histocompatibility antigen HLA; Host-Microbe Biology; Infections; Inflammatory bowel disease; Major histocompatibility complex; Monoclonal antibodies; Morbidity; Mortality; Polymorphism; Recurrent infection; Single-nucleotide polymorphism; Toxin B
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/mSphere.00232-20

Bezlotoxumab is a human monoclonal antibody against toxin B, indicated to prevent recurrence of infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP and the HLA alleles and , located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds toxin B and is indicated for the prevention of recurrent infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of infection recurrence.