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Could diphtheria become a threat again?

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This relatively easily preventable infection is evolving to become resistant to various classes of antibiotics. A team of researchers from the UK and India warns why the vaccine should be regularly re-evaluated in the future.

Diphtheria, a relatively easily preventable infection, is evolving to become resistant to various classes of antibiotics and, in the future, could lead to vaccine failure. This is warned by an international team of researchers from the United Kingdom and India, led by scientists from the University of Cambridge

They ensure that the impact of COVID-19 on diphtheria vaccination programs, along with an increase in the number of infections, runs the risk that the disease will once again become a major global threat.

In the UK and other high-income countries, babies are vaccinated against the infection. However, in low- and middle-income countries, the disease can still cause sporadic infections or outbreaks in unvaccinated or partially vaccinated communities.

The number of reported diphtheria cases globally has gradually increased. In 2018, 16,651 cases were reported, more than double the annual average for 1996-2017 (8,105 cases).

Diphtheria is mainly caused by the bacteria Corynebacterium diphtheriae and is spread mainly by coughing and sneezing, or by close contact with someone who is infected. 

In most cases, the bacteria cause acute infections, driven by diphtheria toxin, which is the key target of the vaccine. However, nontoxigenic C. diphtheria can also cause disease, often in the form of systemic infections.

In a study published in the specialized medium Nature, an international team of researchers from the United Kingdom and India used genomics to map infections, including a subset of India, where more than half of the cases reported globally occurred in 2018.

By analyzing the genomes of 61 bacteria isolated from patients and combining them with 441 publicly available genomes, the researchers were able to construct a phylogenetic tree, a genetic “family tree,” to see how infections are related and understand how they spread. They also used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation.

The researchers found groups of genetically similar bacteria isolated from various continents, most commonly from Asia and Europe. This indicates that C. diphtheriae has been established in the human population for at least a little over a century, spreading throughout the world as populations migrate.

The main disease-causing component of C. diphtheriae is diphtheria toxin, which is encoded by the tox gene. This is the component that vaccines target. In all, the researchers found 18 different variants of the tox gene, several of which had the potential to change the structure of the toxin.

Professor Gordon Dougan, of the Institute of Immunology and Infectious Diseases Therapeutics of Cambridge (CITIID), warned:

The diphtheria vaccine is designed to neutralize the toxin, so any genetic variant that changes its structure could have an impact on the effectiveness of the vaccine. While our data do not suggest that this is happening, the fact that we are detecting an increasing diversity of toxin variants suggests that the vaccine and the treatments that target it should be reassessed on a regular basis.

Diphtheria infections can usually be treated with several classes of antibiotics. Although antibiotic-resistant C. diphtheriae has been reported, the degree of such resistance remains largely unknown.

When the team looked for genes that could confer some degree of antimicrobial resistance, they found that the average number of RAM genes per genome increased every decade. Bacterial genomes isolated from infections in the most recent decade (2010-19) showed the highest average number of AMR genes per genome, almost four times more on average than in the next highest decade, the 1990s.

Robert Will, first author of the study, commented: 

The genome of C. diphtheriae is complex and incredibly diverse. You are becoming resistant to antibiotics that are not even used clinically in the treatment of diphtheria. There must be other factors at play, such as an asymptomatic infection and exposure to a plethora of antibiotics intended to treat other diseases.

The erythromycin and penicillin are the antibiotics of choice traditionally recommended for treating confirmed cases of diphtheria in early stage, but there are several different classes of antibiotics available to treat the infection.

Pankaj Bhatnagar from the World Health Organization India, said:

“Antimicrobial resistance (AMR) has rarely been considered a major problem in the treatment of diphtheria, but in some parts of the world, bacterial genomes are becoming resistant to numerous classes of antibiotics. There are likely several reasons for this, including exposure of the bacteria to antibiotics in their environment or in asymptomatic patients being treated for other infections.”

Researchers say that COVID-19 has had a negative impact on childhood immunization schedules around the world and comes at a time when the number of reported cases is increasing – in fact, 2018 figures are showing the highest incidence in 22 years.

Ankur Mutreja, who led the study, said:

It is more important than ever that we understand how diphtheria evolves and spreads. Genome sequencing gives us a powerful tool to observe this in real-time, allowing public health agencies to take action before it is too late, otherwise, we risk it becoming a new major global threat. , with a potentially better adapted virulence.

Image Credit: Getty

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