Summary
Diphtheria is a historical and vaccine preventable disease (VPD) that is on the rise. Diphtheria vaccine, a toxoid formulation, which is part of every nation’s childhood vaccination program and diphtheria anti toxin (DAT), used in treating severe diphtheria, are both based on just one strain type.
We recently discovered several new variants of diphtheria toxin (DT) with mutations that highly impact the structure of diphtheria toxin. Most of the significant toxin mutations were found in strains collected from India, where the highest number of diphtheria cases have been consistently reported over the last few years.
In this project, we would sequence and analyse a collection of 506 Corynebacterium diphtheriae strains, isolated from patients in India since 2015. The isolates representing toxin variants would be selected for DT expression and purification. Any change in toxin variants’ binding efficiency against the currently used DAT would be assessed and the data from this study would be used as a proof-of-concept for bigger global study.
This work is likely to encourage a long pending dialogue on re-assessing both diphtheria vaccine and treatment landscapes.
Project Outcomes
Diphtheria is a historical and vaccine preventable disease (VPD) that is on the rise. Diphtheria vaccine, a toxoid formulation, which is part of every nation’s childhood vaccination program and diphtheria anti toxin (DAT), used in treating severe diphtheria, are both based on just one strain - PW8.
Recently, we identified 18 different variants of diphtheria toxin (DT) with few having the mutations that had a high, moderate, or low impact on the structure of the toxin. The majority of these toxin variants were discovered in strains obtained from India, where the biggest number of cases of diphtheria have consistently been recorded over the past few years. Although AMR is not a concern right now, administering first-line empirical antibiotics as a treatment option will likely become more challenging in the years to come due to the evolving resistance trend.
We were able to successfully identify seven distinct toxin variants that may have an impact on existing treatment options, and those that represented the toxin protein mutation were DT expressed and purified. Our findings from the BactiVac project indicate that DAT produced against the PW8 vaccination strain of C. diphtheriae has a decreased affinity for the diphtheria toxin variants of C. diphtheriae and all C. ulcerans. Based on this in-vitro evidence and the increasing incidence of strains with such toxin variants raises the possibility of vaccine escape and lower antitoxin treatment efficacy globally.
Using the results of this study as a proof-of-concept, we have recently been able to secure additional funding from ICMR (an Indian funding organisation) for a period of three years. The funding will allow screening and sequencing of more diphtheria toxin variant strains.