Diphtheria is a bacterial infection caused by toxin-producing strains of Corynebacterium diphtheriae and, less commonly, related species like C. ulcerans. Once among the leading killers of children worldwide, it was brought under control by mass vaccination beginning in the 1920s, yet it has never been eradicated. Outbreaks continue to flare in regions with fragile health infrastructure, and the treatment landscape is more precarious than most people realize. The story of diphtheria stretches from nineteenth-century breakthroughs in immunology to twenty-first-century genomic surveillance and even cancer therapy, making it one of the most scientifically rich infectious diseases in modern medicine.
How the Toxin Attacks Human Cells
The danger of diphtheria comes not from the bacterium spreading through your bloodstream but from a single protein it secretes: diphtheria toxin. The bacterium typically stays put in the throat or on the skin, but the toxin it releases travels through the circulation and damages distant organs. At the molecular level, diphtheria toxin targets a protein called elongation factor 2 (eEF2), which is essential for cells to build new proteins. The toxin chemically modifies eEF2 by attaching a small molecular tag to it, a process called ADP-ribosylation, which locks up the cell’s protein-making machinery and eventually kills the cell.1PubMed Central. ADP-ribosylation of translation elongation factor 2 by diphtheria toxin in yeast inhibits translation and cell separation The modification happens at a unique spot on eEF2 called the diphthamide residue, a feature found in virtually all animal cells, which is why the toxin can damage so many different tissues.2Biochemistry. Transition State Structure for ADP-Ribosylation of Eukaryotic Elongation Factor 2 Catalyzed by Diphtheria Toxin
What makes this mechanism so devastating is its efficiency. A single molecule of diphtheria toxin can disable enough eEF2 inside a cell to shut down protein production entirely. The heart, nerves, and kidneys are particularly vulnerable, and much of what we think of as “diphtheria” is really the downstream damage from this toxin circulating through the body rather than the infection itself.
What the Disease Looks Like
Respiratory diphtheria, the classic and most dangerous form, typically begins in the throat. The bacterium grows on the tissues of the pharynx, tonsils, larynx, or nasal passages, producing a thick, grayish pseudomembrane that can obstruct the airway.3PubMed. The pathology of diphtheria In severe cases, this membrane extends into the larynx and trachea, creating a life-threatening obstruction that was, before modern medicine, one of the most feared ways for a child to die.
But the local infection is only part of the picture. As the toxin enters the bloodstream, it targets the heart and nervous system with particular ferocity. Diphtheritic myocarditis, inflammation of the heart muscle caused by the toxin, is the most common cause of death in diphtheria.4Cardiovascular Journal of Africa. Diphtheritic myocarditis: a case report, with toxin-mediated complications and multi-organ involvement It can present as heart failure, dangerous rhythm disturbances, and cardiogenic shock. One study of 60 patients with diphtheria-related heart changes found abnormal heart rhythms in most patients, and a case fatality rate of 25%.5PubMed. Cardiac complications in diphtheria and predictors of outcomes
Neurological complications tend to appear later, sometimes weeks after the initial infection. The toxin damages the insulating sheath around nerves, a process that can cause weakness, difficulty swallowing, and even paralysis. A prospective study of diphtheria patients found that the nerve damage was more varied than textbooks traditionally suggested: while classic teaching describes a purely demyelinating disease, most patients in this study actually showed damage to the nerve fibers themselves rather than just their insulation, with the most severe cases showing complete destruction of both.6PubMed Central. Prospective Study of Diphtheria for Neurological Complications
Cutaneous Diphtheria
Not all diphtheria attacks the throat. Cutaneous diphtheria, where the bacterium infects the skin, is increasingly recognized, especially in travelers and people experiencing homelessness. A retrospective study of cutaneous diphtheria cases in France between 2018 and 2022 found that skin lesions appeared on the lower limbs in the vast majority of cases and typically presented as ulcers. About 39% of isolates were toxin-producing, and most wounds also harbored other bacteria like Staphylococcus aureus and Streptococcus pyogenes.7Emerging Microbes & Infections. Cutaneous diphtheria from 2018 to 2022: an observational, retrospective study of epidemiological, microbiological, clinical, and therapeutic characteristics in metropolitan France Cutaneous diphtheria is generally less dangerous than the respiratory form because the toxin is absorbed more slowly through the skin, but it can still spread to others and seed respiratory infections in contacts.
The Birth of Antitoxin Therapy
Diphtheria holds a special place in the history of medicine as the disease that proved immunotherapy could work. In 1890, researchers developed equine diphtheria antitoxin (eDAT) by injecting horses with increasing doses of diphtheria toxin, then harvesting antibodies from their blood. This approach, now more than 130 years old, remains the cornerstone of treatment for toxin-related complications.8PubMed Central. Diphtheria antitoxin treatment: from pioneer to neglected The early successes with antitoxin therapy helped launch the entire field of serum therapy and inspired work on other antitoxins and eventually vaccines.
Prevention took another leap in the 1920s, when researchers found they could inactivate diphtheria toxin with formaldehyde, creating a toxoid that was safe to inject but still trained the immune system to recognize the real toxin. This formaldehyde-detoxified toxoid became the basis for mass immunization and is considered one of the first great conquests of vaccination.9SpringerLink. History of Diphtheria Vaccine Development The same basic technology, with updates to formulation and combination with other antigens, is still used in today’s DTaP and Tdap vaccines.
Waning Immunity and the Return of Outbreaks
Vaccination drove diphtheria incidence down dramatically across the globe, but the disease never disappeared. Where vaccination coverage drops, outbreaks return with disturbing speed. A 2025 report described a national diphtheria outbreak declared in Somalia, driven by conflict-related displacement, fragile health infrastructure, and uneven immunization coverage.10PubMed Central. Diphtheria outbreak in Somalia: a weekly sitrep on the recent health crisis-2025 A large outbreak among Rohingya refugees in Bangladesh between 2017 and 2019 demonstrated the same pattern: high population density, poor living conditions, and rapid population growth fueled explosive expansion of the disease.11PLOS Medicine. Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox’s Bazar, Bangladesh, 2017 to 2019
Even in populations with some vaccination history, immunity fades over time. A study of displaced populations in Yemen found that overall protection against diphtheria was about 76%, but among adults over 40, nearly two-thirds lacked protective antibody levels.12International Journal of Infectious Diseases Regions. Critical immunity gaps: Waning diphtheria protection among Yemen’s displaced populations calls for urgent booster strategies Research on Portuguese women suggested that adults who completed the full childhood vaccination schedule might maintain protection for 20 years or longer without a booster, but the authors cautioned that this depends on factors like whether toxin-producing strains are still circulating in the community.13PubMed Central. Levels of diphtheria and tetanus specific IgG of Portuguese adult women, before and after vaccination with adult type Td. Duration of immunity following vaccination The practical takeaway is that adults in high-income countries are often more vulnerable than they assume, especially if they have not had a booster in decades.
The Antitoxin Shortage
Here is where diphtheria’s story takes a troubling turn. Treating respiratory diphtheria requires prompt administration of equine diphtheria antitoxin to neutralize the toxin before it does irreversible damage. Antibiotics alone are not enough; they kill the bacterium but do nothing about toxin already circulating in the blood. Yet there is a global shortage of equine antitoxin.14PubMed Central. Characterization of serum anti-diphtheria antibody activity following administration of equine anti-toxin for suspected diphtheria Surveys of manufacturers and procurement agencies have found that prices and availability vary widely, demand is almost impossible to predict for both manufacturers and health agencies, and there are substantial concerns about whether enough antitoxin can be obtained to respond to the increasing number of global outbreaks.15Emerging Infectious Diseases. Diphtheria Antitoxin Production and Procurement Practices and Challenges
The production process itself is part of the problem. Making equine antitoxin requires hyperimmunizing horses, bleeding them, purifying the serum, and testing it. The process is slow, expensive, and yields a product that can cause allergic reactions in patients because it comes from an animal source. The fact that this 130-year-old technology is still the front-line treatment speaks to the neglect diphtheria has suffered in the drug-development pipeline. Because the disease is rare in wealthy countries, there has been little commercial incentive to modernize treatment.
Monoclonal Antibodies as a Modern Replacement
One of the most promising advances is the development of human monoclonal antibodies to replace equine antitoxin. Researchers have isolated monoclonal antibodies directly from immunized human volunteers that can neutralize diphtheria toxin with extraordinary potency. The lead candidate in one study, an antibody called 315C4, was effective at very low concentrations in laboratory tests and completely protected guinea pigs from lethal doses of toxin.16PubMed Central. Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication Because these antibodies are fully human, they would be expected to cause far fewer allergic reactions than horse-derived antitoxin, and they could be produced more reliably at scale. This work is still in development, but it represents the most significant potential upgrade to diphtheria treatment in over a century.
Antibiotic Treatment and Resistance
Antibiotics play a supporting role in diphtheria treatment: they eliminate the bacterium from the throat or skin, stopping further toxin production and reducing transmission. Penicillin and erythromycin are the standard choices. A study of C. diphtheriae isolates from British Columbia found no evidence of penicillin resistance at either the laboratory or genetic level, which is reassuring.17PubMed Central. Phenotypic and Genotypic Correlates of Penicillin Susceptibility in Nontoxigenic Corynebacterium diphtheriae, British Columbia, Canada, 2015-2018
The picture is less comfortable elsewhere. A study of Brazilian C. diphtheriae strains found penicillin resistance in about 15% of isolates tested, and a small proportion showed decreased susceptibility to erythromycin. Many strains displayed resistance to multiple antibiotics.18Memórias do Instituto Oswaldo Cruz. Antimicrobial resistance among Brazilian Corynebacterium diphtheriae strains This is not yet a crisis on the scale of antibiotic resistance in some other pathogens, but it is a reminder that the bacterial side of diphtheria treatment cannot be taken for granted either, especially in regions where outbreaks are recurring.
Diagnosing Diphtheria in 2025
Confirming a case of diphtheria is surprisingly old-fashioned. The recommended test for determining whether a Corynebacterium isolate produces diphtheria toxin is the Elek test, a laboratory method that has been in use for decades despite all the advances in molecular diagnostics.19PubMed Central. Challenges of Diphtheria Toxin Detection The Elek test works by growing the bacterium on a plate with a strip soaked in antitoxin; if the strain produces toxin, a visible line of precipitation forms where the toxin and antitoxin meet. It is reliable but slow, taking one to two days.
Real-time PCR assays can detect the gene for diphtheria toxin much faster and have shown strong accuracy. A triplex PCR assay was able to characterize Corynebacterium isolates with 100% analytical sensitivity and could work directly on clinical specimens, cutting the time to a preliminary result from days to hours.20PubMed Central. Detection and Characterization of Diphtheria Toxin Gene-Bearing Corynebacterium Species through a New Real-Time PCR Assay The catch is that having the toxin gene does not guarantee the bacterium is actually producing toxin. Some strains carry the gene but do not express it. For this reason, culture-based diagnostics remain the gold standard for final case confirmation, even as PCR provides a valuable rapid screen.
Nontoxigenic Strains and Zoonotic Transmission
One of the less intuitive aspects of diphtheria is that C. diphtheriae strains lacking the toxin gene can still cause serious disease. Nontoxigenic strains do not produce the pseudomembrane or cause the systemic toxin damage that defines classic diphtheria, but they can invade the bloodstream and infect heart valves. A cluster of five cases of nontoxigenic C. diphtheriae endocarditis in South Africa had an aggressive course, with only one of five patients surviving to hospital discharge.21PubMed Central. Non-toxigenic Corynebacterium diphtheriae endocarditis: A cluster of five cases An earlier series from Australia similarly highlighted the aggressive nature of this infection, with septic arthritis and major vascular complications appearing in multiple patients.22Clinical Infectious Diseases. Infective Endocarditis Due to Nontoxigenic Corynebacterium diphtheriae: Report of Seven Cases and Review These infections are not prevented by the diphtheria vaccine, which targets only the toxin.
There is also a zoonotic dimension. Corynebacterium ulcerans, a related species that can carry the diphtheria toxin gene, has been transmitted from domestic animals to humans. Cases of zoonotic diphtheria caused by toxigenic C. ulcerans have been confirmed in Spain through genomic analysis linking human and animal isolates, underscoring an animal reservoir that vaccination campaigns aimed at humans cannot reach.23PubMed Central. Zoonotic Transmission of Diphtheria from Domestic Animal Reservoir, Spain
Genomic Surveillance and What It Reveals
Whole-genome sequencing has transformed our understanding of how diphtheria strains are related and how they spread. A core genome typing scheme built from over 1,300 genes and applied to more than 600 isolates revealed 151 distinct sublineages of C. diphtheriae, most of which are geographically restricted to one country or a small cluster of neighboring countries.24PubMed Central. Genomic Epidemiology and Strain Taxonomy of Corynebacterium diphtheriae The same analysis uncovered cryptic transmission chains that would have been invisible to traditional epidemiology and showed that the toxin gene can be gained or lost on surprisingly short evolutionary timescales. This means a nontoxigenic strain circulating harmlessly in a community could, in principle, pick up the toxin gene and become dangerous.
A broader global genomic analysis identified 245 sublineages overall and found that about a third of genomes in the dataset carried the toxin gene. Strikingly, among those that did, an estimated 16% were predicted not to actually produce functional toxin, further complicating the relationship between carrying the gene and causing classic disease.25Peer Community Journal. A global Corynebacterium diphtheriae genomic framework sheds light on current diphtheria reemergence The two major phylogenetic lineages of C. diphtheriae, known as Gravis and Mitis, showed strikingly different profiles of genes associated with causing disease, suggesting that the species is not a monolith but a diverse population with varying potential for harm.
Outbreak Response in Difficult Settings
Controlling diphtheria outbreaks requires a combination of contact tracing, antibiotic prophylaxis for close contacts, and rapid vaccination campaigns. These measures are challenging under the best circumstances and become far harder in settings like refugee camps and correctional facilities. A report on three successive diphtheria outbreaks at a correctional facility in South Africa between 2023 and 2025 highlighted the barriers posed by overcrowding, high population turnover, and the lack of adult vaccination guidelines for incarcerated people and staff.26PubMed Central. Public Health Response to Toxigenic Respiratory Diphtheria Outbreaks at Correctional Facility, South Africa, 2023-2025 The recurring nature of these outbreaks suggests that one-off responses are not enough; systematic vaccination of adults in institutional settings is needed to break the cycle.
Diphtheria Toxin Repurposed Against Cancer
In one of the stranger twists in infectious disease history, the very property that makes diphtheria toxin so lethal has been harnessed as a weapon against cancer. Because the toxin is extremely efficient at killing cells, researchers have engineered versions that are fused to molecules that target specific cancer cells. By replacing the part of the toxin that binds to normal human cells with a targeting molecule that binds only to tumor cells, the engineered toxin becomes a guided missile that kills cancer cells while largely sparing healthy tissue. Two such drugs built on diphtheria toxin have received FDA approval for clinical use.27PubMed Central. Targeted Diphtheria Toxin-Based Therapy: A Review Article The first of these, a fusion of diphtheria toxin with human interleukin-2, was approved for the treatment of cutaneous T-cell lymphoma, a type of skin cancer whose malignant cells display the IL-2 receptor on their surface.28PubMed Central. Immunotoxins for targeted cancer therapy The idea that one of humanity’s oldest bacterial enemies could become a tool in cancer therapy would have been unimaginable to the physicians who first struggled against diphtheria in the nineteenth century, and research into new diphtheria-toxin-based therapies for other malignancies continues.