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

Abstract

Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile 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 rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, 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). IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile 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 C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile 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 C. difficile infection recurrence.

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

“…These studies could be confounded though by additional factors, such as differences in the toxin-gene content of the patient strains. Interestingly, single nucleotide polymorphisms (SNPs) in the human genome, SNP rs2516513, and the HLA alleles HLA-DRB1 * 07:01 and HLA-DQA1 * 02:01 were found to reduce bezlotoxumab treatment efficacy (Shen et al, 2020). These discoveries emphasize the need for GWAS analyses in phase 3 studies and reaffirm the importance of host factors in the immune responses in infectious CDI.…”

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

“…In fact, several reports show that defective B responses might be an important factor in C. difficile disease recurrence. Low concentrations of neutralizing anti‐TcdB and anti‐TcdA Abs, 88 memory B cell‐encoded Abs with low to moderate affinity for TcdB, and limited ability to neutralize TcdB, 89 as well as host genetic variations located in the extended major histocompatibility complex, 90 have been proposed to explain recurrent CDI.…”

Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

“…The single nucleotide polymorphism rs2516513 and the human leukocyte antigen alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, which are located in the extended major histocompatibility complex on chromosome 6, showed an association with a reduced risk of rCDI in patients treated with bezlotoxumab. Notably, the same was not observed in patients receiving placebo [64]. Finally, the protective effect of bezlotoxumab was confirmed in a subgroup analysis of Japanese patients enrolled in the MODIFY trials [65].…”