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Diphtheria could become major global threat again, warn University of Cambridge researchers

Diphtheria could once again become a major global threat, an international team led by University of Cambridge scientists have warned.

It is evolving to become resistant to a number of classes of antibiotics, and this in future could enable it to escape vaccines.

A diphtheria vaccination
A diphtheria vaccination

The impact of Covid-19 on diphtheria vaccination schedules and a rise in the number of infections has raised the threat this highly contagious infection poses.

Primarily, diphtheria is caused by the bacterium Corynebacterium diphtheriae, which is spread by coughs and sneezes, or close contact with an infected person. It affects the nose and threat, and sometimes the skin. Untreated, it can prove fatal.

Babies are vaccinated against diphtheria in the UK and other high-income countries. But in low and middle-income countries, there are sporadic outbreaks in unvaccinated or partially vaccinated communities.

There were 16,651 cases reported globally in 2018 - more than double the yearly average of 8,105 in 1996-2017.

An international team of researchers from the UK and India used genomics to map infections, which included a subset from India, where more than half the globally reported cases occurred in 2018.

They built a phylogenetic tree – a genetic family tree – to understand how the infections were related, showing that C. diphtheriae has been established in the human population for more than a century, spreading across the globe as populations migrated.

The main disease-causing component is the diphtheria toxin, which is encoded by the tox gene, which is targeted by vaccines. The researchers found 18 different variants of the tox gene - and several had the potential to change the structure of the toxin.

Non-toxigenic C. diphtheria can also cause disease, often in the form of systemic infections.

Professor Gordon Dougan, of the Wellcome Sanger Institute. Picture: Sanger Insitute - Wellcome Trust. Photo by Phil Mynott (11312373)
Professor Gordon Dougan, of the Wellcome Sanger Institute. Picture: Sanger Insitute - Wellcome Trust. Photo by Phil Mynott (11312373)

Professor Gordon Dougan, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), said: “The diphtheria vaccine is designed to neutralise the toxin, so any genetic variants that change the toxin’s structure could have an impact on how effective the vaccine is. While our data doesn’t suggest the currently used vaccine will be ineffective, the fact that we are seeing an ever-increasing diversity of tox variants suggests that the vaccine, and treatments that target the toxin, need to be appraised on a regular basis.”

A number of classes of antibiotics can be used to treat diphtheria infections. There have been reports of C. diphtheriae resistance to them, but the extent remains unknown.

The researchers found the average number of anti-microbial resistant genes per genome was, however, increasing each decade - four times as many in 2010-19 as in the 1990s.

Robert Will, a PhD student at CITIID and the study’s first author, said: “The C. diphtheriae genome is complex and incredibly diverse. It’s acquiring resistance to antibiotics that are not even clinically used in the treatment of diphtheria. There must be other factors at play, such as asymptomatic infection and exposure to a plethora of antibiotics meant for treating other diseases.”

Dr Ankur Mutreja from CITIID, who led the study, said: “It’s more important than ever that we understand how diphtheria is evolving and spreading. Genome sequencing gives us a powerful tool for observing this in real time, allowing public health agencies to take action before it’s too late.

“We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form.”

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